CDK Inhibitors And Their Use As Pharmaceuticals

ABSTRACT

The disclosure is directed to compounds of Formula I 
     
       
         
         
             
             
         
       
     
     Pharmaceutical compositions comprising compounds of Formula I, as well as methods of their use and preparation, are also described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/081,126, filed Sep. 21, 2020, the entirety of which is incorporatedby reference herein, and U.S. Provisional Application No. 63/221,959,filed Jul. 15, 2021, the entirety of which is incorporated by referenceherein.

TECHNICAL FIELD

The disclosure is directed to CDK inhibitors and methods of their use.

BACKGROUND

Cyclin-dependent kinases (CDKs) are a family of conservedserine/threonine kinases that play critical roles in cell cycle and genetranscription regulation (Malumbres 2014). Among the cell cycle CDKsubfamily, CDK4 and CDK6 are the master regulators that control entry ofcells from the first gap phase (G1) to the DNA synthesis phase (S).During this process, cyclin D protein levels increase, complex withCDK4/6 and activate their kinase activities. Activated CDK4/6 complexesphosphorylate retinoblastoma protein (RB1) and other RB1-like proteins,reduce their binding affinities and release RB1-containing transcriptionrepressor complexes from E2F transcription factors, resulting inactivation of E2F controlled cell cycle genes and progression of cellcycle (Lapenna and Giordano 2009, Asghar, Witkiewicz et al. 2015).

Given the central roles CDK4/6 play in cell cycle regulation,disfunction of which is a hallmark of cancer (Hanahan and Weinberg2011), dysregulation of CDK4/6 pathway has been frequently observed incancer, such as (epi)genetic inactivation of endogenous CDK4/6 inhibitorp16INK4A and amplification/overexpression of CDK4/6 as well as cyclin Dproteins (Lapenna and Giordano 2009, Malumbres and Barbacid 2009,Asghar, Witkiewicz et al. 2015, O'Leary, Finn et al. 2016). CDK4/6 havebeen intensively investigated as potential therapeutic targets forcancer treatment and the recent approval of CDK4/6 selective inhibitors,namely, Palbociclib (U.S. Food & Drug Administration. 2017), Ribociclib(U.S. Food & Drug Administration. 2017), and Abemaciclib (U.S. Food &Drug Administration. 2018), in combination with endocrine therapies, totreat hormone receptor (HR) positive and human epidermal growth factorreceptor 2 (HER2) negative metastatic breast cancer further validatedthis thesis.

Central nervous system (CNS) diseases such as glioblastoma (GBM) andbrain metastases are challenging malignancies with urgent unmet needs.GBM is the most common and aggressive primary brain cancer in adultswith overall 5-year survival rate less than 6% (Ostrom, Gittleman et al.2016). Large scale genomic studies revealed that the cyclin D-CDK4/6-RB1pathway is alternated in majority of gliomas and represents one of themost perturbed pathways (Cancer Genome Atlas Research 2008, Brennan,Verhaak et al. 2013), suggesting CDK4/6 may be good targets for GBM.Brain metastases, on the other hand, may arise from an estimated of 20%of all cancer patients but still lacks effective treatments (Achrol,Rennert et al. 2019). Interestingly, genomic studies also identified CDKpathway as one of three most altered and actionable genetic alternationsin brain metastases (Brastianos, Carter et al. 2015, Valiente, Ahluwaliaet al. 2018).

However, despite positive preclinical data supporting targeting CDK4/6to treat GBM (Yin, Li et al. 2018, Bronner, Merrick et al. 2019), andinitial signs of brain penetration of Abemaciclib in patients (Patnaik,Rosen et al. 2016, Sahebjam, Rhun et al. 2016), clinical development ofCDK4/6 inhibitors in the clinic for GBM or brain metastases are still inearly stage or unsuccessful (Anders, Rhun et al. 2019, Nguyen, Searle etal. 2019, Sahebjam, Le Rhun et al. 2019), likely due to their inabilityto penetrate the blood-brain barrier (BBB) (de Gooijer, Zhang et al.2015, Parrish, Pokorny et al. 2015, Raub, Wishart et al. 2015).

Additional small molecule CDK4/6 inhibitors are needed.

SUMMARY OF THE INVENTION

The disclosure is directed to compounds of Formula I.

or a pharmaceutically acceptable salt thereof, wherein

ring A is a 5-7-membered heteroaryl;

V=CL₁R₁ or Nn is 1 or 2 or 3;

m is 1 or 2;

o is 1, 2, 3, 4, or 5;

each L₁ is independently a bond, O, NR or C₁-C₆ alkylene, wherein R is Hor C₁-C₆alkyl;

each R₁ is independently H, D, halogen, —OH, —CN, —NO₂, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR^(a), —SR^(a),—NR^(c)R^(d), —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(d), —S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅,—P(O)R^(b)R^(b), —P(O)(OR^(b))(OR^(b)), —B(OR^(c))(OR^(d)) or—S(O)₂R^(b);

each R₂ is independently H, D, halogen, C₁-C₈ alkoxide C₁-C₈ alkyl,haloalkyl, or CN and

each R₃ is independently H, D, halogen, oxo, —OH, —CN, —NO₂,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, C₀-C₁alk-aryl,C₀-C₁alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, —OR^(a), —OR^(b), SR^(b), —NR^(c)R^(d),—NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(d),—S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅, —P(O)R^(b)R^(b),—P(O)(OR^(b))(OR), —B(OR^(d))(OR^(c)) or —S(O)₂R^(b);

each R^(a) is independently H, D, —C(O)R^(b), —C(O)OR^(c),—C(O)NR^(c)R^(d), —C(═NR)NR^(b)R^(c), —C(═NOR^(b))NR^(b)R^(c),—C(═NCN)NR^(b)R^(c), —P(OR^(c))₂, —P(O)R^(c)R^(b), —P(O)OR^(c)R^(b),—S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b), —S(O)₂NR^(c)R^(d), SiR₃,—C₁-C₁₀alkyl, —C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl,cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;

each R^(b), is independently H, D, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl,or heterocycloalkenyl;

each R^(c) or R^(d) is independently H, D, —C₁-C₁₀ alkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

or R^(c) and R^(d), together with the atom to which they are bothattached, form a monocyclic or multicyclic heterocycloalkyl, or amonocyclic or multicyclic heterocyclo-alkenyl group;

each R₄ is independently H, D, halogen, C₁-C₈ alkoxide or C₁-C₈ alkyl,haloalkyl and CN.

Stereoisomers of the compounds of Formula I, and the pharmaceuticalsalts and solvates thereof, are also contemplated, described, andencompassed herein. Methods of using compounds of Formula I aredescribed, as well as pharmaceutical compositions including thecompounds of Formula I.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following definitions and examples.Certain features of the disclosed compositions and methods which aredescribed herein in the context of separate aspects, may also beprovided in combination in a single aspect. Alternatively, variousfeatures of the disclosed compositions and methods that are, forbrevity, described in the context of a single aspect, may also beprovided separately or in any subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁-C₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl. “C₀alkyl” refers to a covalent bond.

It is further intended that the compounds of the invention are stable.As used herein “stable” refers to a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and preferably capable of formulation into an efficacioustherapeutic agent.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub-combination.

The term “alkyl,” when used alone or as part of a substituent group,refers to a straight- or branched-chain hydrocarbon group having from 1to 12 carbon atoms (“C₁-C₁₂”), preferably 1 to 6 carbons atoms(“C₁-C₆”), in the group. Examples of alkyl groups include methyl (Me,C₁alkyl), ethyl (Et, C₂alkyl), n-propyl (C₃alkyl), isopropyl (C₃alkyl),butyl (C₄alkyl), isobutyl (C₄alkyl), sec-butyl (C₄alkyl), tert-butyl(C₄alkyl), pentyl (C₅alkyl), isopentyl (C₅alkyl), tert-pentyl (C₅alkyl),hexyl (C₆alkyl), isohexyl (C₆alkyl), and the like. Alkyl groups of thedisclosure can be unsubstituted or substituted. In those embodimentswherein the alkyl group is substituted, the alkyl group can besubstituted with 1, 2, or 3 substituents independently selected from—OH, —CN, amino, halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy. Additional substitutents include —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), and —S(O)₂N(C₁-C₆alkyl)₂.

The term “halo” or halogen, refers to chloro, fluoro, bromo, or iodo.

The term “cycloalkyl” when used alone or as part of a substituent grouprefers to cyclic-containing, non-aromatic hydrocarbon groups having from3 to 10 carbon atoms (“C₃-C₁₀”), preferably from 3 to 6 carbon atoms(“C₃-C₆”). Cycloalkyl groups of the disclosure include monocyclicgroups, as well as multicyclic groups such as bicyclic and tricyclicgroups. In those embodiments having at least one multicyclic cycloalkylgroup, the cyclic groups can share one common atom (i.e., spirocyclic).In other embodiments having at least one multicyclic cycloalkyl group,the cyclic groups share two common atoms. Examples of cycloalkyl groupsinclude, for example, cyclopropyl (C₃), cyclobutyl (C₄),cyclopropylmethyl (C₄), cyclopentyl (C₅), cyclohexyl (C₆),1-methylcyclopropyl (C₄), 2-methylcyclopentyl (C₄), adamantanyl (C₁₀),spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, and the like. Cycloalkylgroups of the disclosure can be unsubstituted or substituted. In thoseembodiments wherein the cycloalkyl group is substituted, the cycloalkylgroup can be substituted with 1, 2, or 3 substituents independentlyselected from —OH, —CN, amino, halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy. Additional substitutents include—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆alkyl),—OC(O)N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), and —S(O)₂N(C₁-C₆alkyl)₂.

The term “heterocycloalkyl” when used alone or as part of a substituentgroup refers to any three to ten membered monocyclic or bicyclic,saturated ring structure containing at least one heteroatom selectedfrom the group consisting of O, N and S. Heterocycloalkyl groups of thedisclosure include monocyclic groups, as well as multicyclic groups suchas bicyclic and tricyclic groups. In those embodiments having at leastone multicyclic heterocycloalkyl group, the cyclic groups can share onecommon atom (i.e., spirocyclic). In other embodiments having at leastone multicyclic heterocycloalkyl group, the cyclic groups share twocommon atoms. The term —C₃-C₆ heterocycloalkyl refers to aheterocycloalkyl group having between three and six carbon ring atoms.The term —C₃-C₁₀ heterocycloalkyl refers to a heterocycloalkyl grouphaving between three and 10 rin atoms. The heterocycloalkyl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure. Examples of suitable heterocycloalkylgroups include, but are not limited to, azepanyl, aziridinyl,azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl,piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl,tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, azepanyl, diazepanyl,oxepanyl, dioxepanyl, azocanyl diazocanyl, oxocanyl, dioxocanyl,azaspiro[2.2]pentanyl, oxaazaspiro[3.3]heptanyl, oxaspiro[3.3]heptanyl,dioxaspiro[3.3]heptanyl, and the like. Heteroycloalkyl groups of thedisclosure can be unsubstituted or substituted. In those embodimentswherein the heterocycloalkyl group is substituted, the heterocycloalkylgroup can be substituted with 1, 2, or 3 substituents independentlyselected from —OH, —CN, amino, halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy. Additional substitutents include—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆alkyl),—OC(O)N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), and —S(O)₂N(C₁-C₆alkyl)₂.

The term “heterocycloalkenyl” when used alone or as part of asubstituent group refers to any three to ten membered monocyclic orbicyclic, partially saturated ring structure containing at least oneheteroatom selected from the group consisting of O, N and S.Heterocycloalkenyl groups of the disclosure include monocyclic groups,as well as multicyclic groups such as bicyclic and tricyclic groups. Inthose embodiments having at least one multicyclic heterocycloalkyenylgroup, the cyclic groups can share one common atom (i.e., spirocyclic).In other embodiments having at least one multicyclic heterocycloalkenylgroup, the cyclic groups share two common atoms. The term —C₃-C₆heterocycloalkenyl refers to a heterocycloalkenyl group having betweenthree and six carbon atoms. The term —C₃-C₁₀ heterocycloalkenyl refersto a heterocycloalkenyl group having between three and ten ring atoms.The heterocycloalkenyl group may be attached at any heteroatom or carbonatom of the ring such that the result is a stable structure.Heteroycloalkenyl groups of the disclosure can be unsubstituted orsubstituted. In those embodiments wherein the heterocycloalkenyl groupis substituted, the heterocycloalkenyl group can be substituted with 1,2, or 3 substituents independently selected from —OH, —CN, amino, halo,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, and C₁-C₆haloalkoxy. Additionalsubstitutents include —C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂,—OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), and—S(O)₂N(C₁-C₆alkyl)₂.

The term “heteroaryl” when used alone or as part of a substituent grouprefers to a mono- or bicyclic-aromatic ring structure including carbonatoms as well as up to five heteroatoms selected from nitrogen, oxygen,and sulfur. Heteroaryl rings can include a total of 5, 6, 7, 8, 9, or 10ring atoms. The term —C₅-C₁₀ heteroaryl refers to a heteroaryl groupcontaining five to ten ring atoms. Examples of heteroaryl groups includebut are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyranyl, furazanyl, indolizinyl, indolyl, and the like. Heteroarylgroups of the disclosure can be unsubstituted or substituted. In thoseembodiments wherein the heteroaryl group is substituted, the heteroarylgroup can be substituted with 1, 2, or 3 substituents independentlyselected from —OH, —CN, amino, halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy. Additional substitutents include—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆alkyl),—OC(O)N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), and —S(O)₂N(C₁-C₆alkyl)₂.

The term “aryl” when used alone or as part of a substituent group refersto a mono- or bicyclic-aromatic carbon ring structure. Aryl rings caninclude a total of 5, 6, 7, 8, 9, or 10 ring atoms. Examples of arylgroups include but are not limited to, phenyl, napthyl, and the like.Aryl groups of the disclosure can be unsubstituted or substituted. Inthose embodiments wherein the aryl group is substituted, the aryl groupcan be substituted with 1, 2, or 3 substituents independently selectedfrom —OH, —CN, amino, halo, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, andC₁-C₆haloalkoxy. Additional substitutents include —C(O)NH(C₁-C₆alkyl),—C(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆alkyl)₂,—S(O)₂NH(C₁-C₆alkyl), and —S(O)₂N(C₁-C₆alkyl)₂.

When a range of carbon atoms is used herein, for example, C₁-C₆, allranges, as well as individual numbers of carbon atoms are encompassed,for example, “C₁₋₃” includes C₁₋₃, C₁₋₂, C₂₋₃, C₁, C₂, and C₃. The term“C₁₋₆alk” refers to an aliphatic linker having 1, 2, 3, 4, 5, or 6carbon atoms and includes, for example, —CH₂—, —CH(CH₃)—, —CH(CH₃)—CH₂—,and —C(CH₃)₂—. The term “—C₀alk-” refers to a bond.

The term “C₀-C₆alk” when used alone or as part of a substituent grouprefers to an aliphatic linker having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.The term “—C₁alk-”, for example, refers to a —CH₂—. The term “—C₀alk-”refers to a bond.

As used herein, each —C₁-C₆alkyl, —C₁-C₁₀ alkyl, —C₂-C₆alkenyl,—C₂-C₁₀alkenyl, —C₂-C₆alkynyl, —C₂-C₁₀alkynyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkenyl, and heterocycloalkyl canbe optionally substituted with 1, 2, or 3 substituents independentlyselected from —OH, —CN, amino, halo, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, and C₁-C₆haloalkoxy. Additional substitutents include—C(O)NH(C₁-C₆alkyl), —C(O)N(C₁-C₆alkyl)₂, —OC(O)NH(C₁-C₆alkyl),—OC(O)N(C₁-C₆alkyl)₂, —S(O)₂NH(C₁-C₆alkyl), and —S(O)₂N(C₁-C₆alkyl)₂.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “hydroxylalkyl” refers to an alkyl group substituted byOH.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Geometric isomers of the compounds of the present inventionare described and may be isolated as a mixture of isomers or asseparated isomeric forms.

Compounds of the invention may also include tautomeric forms. Alltautomeric forms are encompassed.

In some embodiments, the compounds of the present invention may exist asrotational isomers. In some embodiments, the compounds of the presentinvention exist as mixtures of rotational isomers in any proportion. Inother embodiments, the compounds of the present invention exist asparticular rotational isomers, substantially free of other rotationalisomers.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds of the invention, and salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compound of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound of Formula Iwith one or more solvent molecules.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Compounds of the present disclosure,” and equivalent expressions, aremeant to embrace compounds of Formula I as described herein, as well asits subgenera, which expression includes the stereoisomers (e.g.,entaniomers, diastereomers) and constitutional isomers (e.g., tautomers)of compounds of Formula I as well as the pharmaceutically acceptablesalts, where the context so permits.

As used herein, the term “isotopic variant” refers to a compound thatcontains proportions of isotopes at one or more of the atoms thatconstitute such compound that is greater than natural abundance. Forexample, an “isotopic variant” of a compound can be radiolabeled, thatis, contain one or more radioactive isotopes, or can be labeled withnon-radioactive isotopes such as for example, deuterium (2H or D),carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understoodthat, in a compound where such isotopic substitution is made, thefollowing atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers,” for example, diastereomers, enantiomers, andatropisomers. The compounds of this disclosure may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)-stereoisomers at each asymmetric center, or asmixtures thereof. Unless indicated otherwise, the description or namingof a particular compound in the specification and claims is intended toinclude all stereoisomers and mixtures, racemic or otherwise, thereof.Where one chiral center exists in a structure, but no specificstereochemistry is shown for that center, both enantiomers, individuallyor as a mixture of enantiomers, are encompassed by that structure. Wheremore than one chiral center exists in a structure, but no specificstereochemistry is shown for the centers, all enantiomers anddiastereomers, individually or as a mixture, are encompassed by thatstructure. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art.

The disclosure is directed to compounds of Formula I:

or a pharmaceutically acceptable salt or solvate or N-oxide thereof;ring A is a 5-7-membered heteroaryl;V=CL₁R₁ or Nn is 1 or 2 or 3;

m is 1 or 2;

o is 1, 2, 3, 4, or 5;

each L₁ is independently a bond, O, NR or C₁-C₆ alkylene, wherein R is Hor C₁-C₆alkyl;

each R₁ is independently H, D, halogen, —OH, —CN, —NO₂, —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —OR^(a), —SR^(a),—NR^(c)R^(d), —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(d), —S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅,—P(O)R^(b)R^(b), —P(O)(OR^(b))(OR^(b)), —B(OR^(c))(OR^(d)) or—S(O)₂R^(b);

each R₂ is independently H, D, halogen, C₁-C₈ alkoxide C₁-C₈ alkyl,haloalkyl, or CN and

each R₃ is independently H, D, halogen, oxo, —OH, —CN, —NO₂,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, C₀-C₁alk-aryl,C₀-C₁alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, —OR^(a), —OR^(b), SR^(b), —NR^(c)R^(d),—NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(d),—S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅, —P(O)R^(b)R^(b),—P(O)(OR^(b))(OR), —B(OR^(d))(OR^(c)) or —S(O)₂R^(b);

each R^(a) is independently H, D, —C(O)R^(b), —C(O)OR^(c),—C(O)NR^(c)R^(d), —C(═NR)NR^(b)R^(c), —C(═NOR^(b))NR^(b)R^(c),—C(═NCN)NR^(b)R^(c), —P(OR^(c))₂, —P(O)R^(c)R^(b), —P(O)OR^(c)R^(b),—S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b), —S(O)₂NR^(c)R^(d), SiR₃,—C₁-C₁₀alkyl, —C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl,cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl;

each R^(b), is independently H, D, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl,or heterocycloalkenyl;

each R^(c) or R^(d) is independently H, D, —C₁-C₁₀ alkyl, —C₂-C₆alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl, aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl;

or R^(c) and R^(d), together with the atom to which they are bothattached, form a monocyclic or multicyclic heterocycloalkyl, or amonocyclic or multicyclic heterocyclo-alkenyl group; each R₄ isindependently H, D, halogen, C₁-C₈ alkoxide or C₁-C₈ alkyl, haloalkyland CN.

In some embodiments, ring A in Formula (I) is a 5-7-membered heteroaryl.In some embodiments, ring A is a 5-membered heteroaryl. In otherembodiments, ring A is a 6-membered heteroaryl. In yet otherembodiments, ring A is a 7-membered heteroaryl.

In some embodiments, ring A is a 5-membered heteroaryl having at leastone N atom. In some embodiments, the 5-membered heteroaryl having atleast one N atom is an imidazole. In other embodiments, ring A is a6-membered heteroaryl having at least one N atom. In other embodiments,the 6-membered heteroaryl having at least two N atom is a pyrimidine ora pyridazine.

In some embodiments, V in Formula (I) is N or CL₁R¹. In someembodiments, V is N. In other embodiments, V is CL₁R¹.

In some embodiments, n in Formula (I) is 1, 2 or 3. In some embodiments,n is 1. In other embodiments, n is 2. In yet other embodiments, n is 3.

In some embodiments, m in Formula (I) is 1 or 2. In some embodiments, mis 1. In other embodiments, m is 2.

In some embodiments, o in Formula (I) is 1, 2, 3, 4 or 5. In someembodiments, o is 1. In some embodiments, o is 2. In other embodiments,o is 3. In other embodiments, o is 4. In yet other embodiments, o is 5.

In some embodiments, each L¹ in Formula I is independently a bond, O, NRor C₁-C₆ alkylene, wherein R is H or C₁-C₆alkyl. In some embodiments, L¹is a bond. In some embodiments, L¹ is O. In some embodiments, L¹ is NR.In some embodiments, L¹ is C₁-C₆ alkylene. In some embodiments, L¹ ismethylene. In some embodiments, R is H. In some embodiments, R isC₁-C₆alkyl. In some embodiments, R is methyl.

In some embodiments, each R₁ in Formula I is independently H, D,halogen, —OH, —CN, —NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, —OR^(a), —SR^(a), —NR^(c)R^(d), —NR^(a)R^(c),—C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(d), —S(O)R^(b),—S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅, —P(O)R^(b)R^(b),—P(O)(OR^(b))(OR^(b)), —B(OR^(c))(OR^(d)) or —S(O)₂R^(b). In someembodiments, R₁ is H. In some embodiments, R₁ is D. In some embodiments,R₁ is halogen. In some embodiments, R₁ is —OH. In some embodiments, R₁is —CN. In some embodiments, R₁ is NO₂. In some embodiments, R₁ is—C₁-C₆alkyl. In some embodiments, R₁ is —C₂-C₆alkenyl. In someembodiments, R₁ is —C₂-C₆alkynyl. In some embodiments, R₁ is aryl. Insome embodiments, R₁ is heteroaryl. In some embodiments, R₁ iscycloalkyl. In some embodiments, R₁ is cycloalkenyl. In someembodiments, R₁ is heterocycloalkenyl. In some embodiments, R₁ is—OR^(a), —SR^(a), —NR^(c)R^(d), —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b),—C(O)OR^(b), —C(O)NR^(c)R^(d), —S(O)R^(b), —S(O)₂NR^(c)R^(d),—S(O)(═NR^(b))R^(b), —SF₅, —P(O)R^(b)R^(b), —P(O)(OR^(b))(OR^(b)),—B(OR^(c))(OR^(d)), —S(O)₂R^(b) and the like.

In other embodiments, R₁ is heterocycloalkyl. In other embodiments, R₁is a 6-membered heterocyclalkyl. In some embodiments, R₁ is apiperazine. In yet other embodiments, R₁ is a 7-memberedheterocyclalkyl. In yet other embodiments, R₁ is a spiro-fused group. Inyet other embodiments, R₁ is a diazaspiroheptane.

In some embodiments, each R₂ in Formula I is independently H, D,halogen, C₁-C₈ alkoxide, C₁-C₈ alkyl, haloalkyl, or —CN. In someembodiments, R₂ is H. In some embodiments, R₂ is D. In otherembodiments, R₂ is halogen. In other embodiments, R₂ is fluoro. In yetother embodiments, R₂ is C₁-C₈ alkoxide. In yet other embodiments, R₂ isC₁-C₈ alkyl. In yet other embodiments, R₂ is haloalkyl. In yet otherembodiments, R₂ is —CN.

In some embodiments, each R₃ in Formula I is independently H, D,halogen, oxo, —OH, —CN, —NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,C₀-C₁alk-aryl, C₀-C₁alk-heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl, —OR^(a), —OR^(b), —SR^(b),—NR^(c)R^(d), —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(d), —S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅,—P(O)R^(b)R^(b), —P(O)(OR^(b))(OR^(b)), —B(OR^(d))(OR^(c)) or—S(O)₂R^(b).

In some embodiments of the disclosure, at least one R₃ moiety will bedirectly bonded to the remainder of the compound of Formula (I) via acarbon atom. In particularly preferred aspects of these embodiments,each R₃ bonded through a carbon atom is independently H, D, halogen,oxo, —OH, —CN, —NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl,C₀-C₁alk-aryl, C₀-C₁alk-heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl, —OR^(a), —OR^(b), —SR^(b),—NR^(c)R^(d), —NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(d), —S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR^(b))R^(b),—SF₅, —P(O)R^(b)R^(b), —P(O)(OR^(b))(OR^(b)), —B(OR^(d))(OR^(c)) or—S(O)₂R^(b).

In some embodiments of the disclosure, at least one R₃ moiety will bedirectly bonded to the remainder of the compound of Formula (I) via anitrogen atom. In particularly preferred aspects of these embodiments,each R₃ bonded through a nitrogen atom is independently H, D, oxo, —OH,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, C₀-C₁alk-aryl,C₀-C₁alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, —OR^(a), —OR^(b), —NR^(c)R^(d), —NR^(a)R^(c),—S(O)₂NR^(d), or —S(O)₂R^(b).

In some embodiments, R₃ is H. In some embodiments, R₃ is D. In someembodiments, R₃ is halogen. In some embodiments, R₃ is oxo. In someembodiments, R₃ is bound to a nitrogen atom and R₃ is oxo. In someembodiments, R₃ is —OH. In some embodiments, R₃ is —CN. In someembodiments, R₃ is NO₂. In some embodiments, R₃ is —C₁-C₆alkyl. In someembodiments, R₃ is —C₂-C₆alkenyl. In some embodiments, R₃ is—C₂-C₆alkynyl. In other embodiments, R₃ is C₀-C₁alk-aryl. In otherembodiments, R₃ is C₀-C₁alk-heteroaryl. In other embodiments, R₃ iscycloalkyl. In other embodiments, R₃ is C₃₋₁₀cycloalkyl. In otherembodiments, R₃ is cycloalkenyl. In other embodiments, R₃ isheterocycloalkyl. In other embodiments, R₃ is heterocycloalkenyl. In yetother embodiments, R₃ is OR^(a), —OR^(b), —SR^(b), —NR^(c)R^(d),—NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(d),—S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅, —P(O)R^(b)R^(b),—P(O)(OR^(b))(OR), —B(OR^(d))(OR^(c)), —S(O)₂R^(b) and the like. In someaspects, at least one R₃ is hydroxyalkyl. In other aspects, R₃ isC₁-C₆alkyl, for example, isopropyl. In other aspects, R₃ is oxo. Inother aspects, R₃ is oxo bound to a nitrogen atom. In some aspects R₃ isOR.

In some embodiments, each R^(a) in Formula I is independently H, D,—C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d), —C(═NR)NR^(b)R^(c),—C(═NOR)NR^(b)R^(c), —C(═NCN)NRR^(c), —P(OR^(c))₂, —P(O)R^(b)R^(b),—P(O)OR^(c)OR^(b), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),—S(O)₂NR^(c)R^(d), SiR₃, —C₁-C₁₀alkyl, —C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl,aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, orheterocycloalkenyl.

In some embodiments, R^(a) is H. In some embodiments, R^(a) is D. Insome embodiments, R^(a) is —C(O)R^(b). In some embodiments, R^(a) is—C(O)OR^(c). In some embodiments, R^(a) is —C(O)NR^(c)R^(d). In someembodiments, R^(a) is —C(═NR)NR^(b)R^(c). In some embodiments, R^(a) isC(═NOR^(b))NR^(b)R^(c). In some embodiments, R^(a) is—C(═NCN)NR^(b)R^(c).

In other embodiments, R^(a) is —P(OR^(c))₂, —P(O)R^(b)R^(b),—P(O)OR^(c)R^(b), —S(O)R^(b), —S(O)NR^(c)R^(d), —S(O)₂R^(b),—S(O)₂NR^(c)R^(d), SiR₃, and the like. In yet other embodiments, R^(a)is —C₁-C₁₀alkyl, —C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl,cycloalkenyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, and thelike.

In some embodiments, each R^(b) in Formula I is independently H, D,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl,cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. Insome embodiments, R^(b) is H. In some embodiments, R^(b) is D. In someembodiments, R^(b) is —C₁-C₆ alkyl. In some embodiments, R^(b) is —C₂-C₆alkenyl. In some embodiments, R^(b) is —C₂-C₆ alkynyl. In otherembodiments, R^(b) is aryl. In other embodiments, R^(b) is cycloalkyl.In other embodiments, R^(b) is cycloalkenyl. In other embodiments, R^(b)is heteroaryl. In other embodiments, R^(b) is heterocycloalkyl. In otherembodiments, R^(b) is heterocycloalkenyl.

In some embodiments, each R^(c) or R^(d) in Formula I is independentlyH, D, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl, cycloalkyl,cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. Insome embodiments, R^(c) or R^(d) is H. In some embodiments, R^(c) orR^(d) is D. In some embodiments, R^(c) or R^(d) is —C₁-C₁₀ alkyl. Insome embodiments, R^(c) or R^(d) is —C₂-C₆ alkenyl. In some embodiments,R^(c) or R^(d) is —C₂-C₆ alkynyl. In other embodiments, R^(c) or R^(d)is —OC₁-C₆alkyl. In other embodiments, R^(c) or R^(d) is —O-cycloalkyl.In other embodiments, R^(c) or R^(d) is aryl. In other embodiments,R^(c) or R^(d) is cycloalkyl. In other embodiments, R^(c) or R^(d) iscycloalkenyl. In other embodiments, R^(c) or R^(d) is heteroaryl. Inother embodiments, R^(c) or R^(d) is heterocycloalkyl. In otherembodiments, R^(c) or R^(d) is heterocycloalkenyl.

In yet other embodiments, R^(c) and R^(d), together with the atom towhich they are both attached, form a monocyclic or multicyclicheterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenylgroup. In yet other embodiments, R^(c) and R^(d) form a monocyclicheterocycloalkyl. In yet other embodiments, R^(c) and R^(d) form amulticyclic heterocycloalkyl. In yet other embodiments, R^(c) and R^(d)form a monocyclic heterocyclo-alkenyl group. In yet other embodiments,R^(c) and R^(d) form a multicyclic heterocyclo-alkenyl group.

In some embodiments, each R₄ in Formula I is independently H, D,halogen, C₁-C₈ alkoxide or C₁-C₈ alkyl, haloalkyl and —CN. In someembodiments, R₄ is H. In some embodiments, R₄ is D. In some embodiments,R₄ is halogen. In some embodiments, R₄ is —C₁-C₈ alkoxide. In otherembodiments, R₄ is —C₁-C₈ alkyl. In other embodiments, R₄ is methyl. Inother embodiments, R₄ is haloalkyl. In other embodiments, R₄ is —CN.

In some embodiments, the compounds of Formula (I) are thepharmaceutically acceptable salts. In some embodiments, the compounds ofFormula (I) are solvates. In some embodiments, the compounds of Formula(I) are N-oxides of the compounds of Formula (I).

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula II

or a pharmaceutically acceptable salt thereof, wherein

each X is independently N, N-oxide or CR₃ and at least one X is N orN-oxide; and wherein each R₄, R₃, (R₂)_(m), V and (L₁R₁)_(n) is definedwith respect to Formula (I).

In some embodiments, each X in Formula II is N. In other embodiments,one X in Formula II is N-oxide and three Xs in Formula II are CR₃. Inother embodiments, one X in Formula II is N and three Xs in Formula IIare CR₃. In yet other embodiments, two Xs in Formula II are N and two Xsin Formula II are CR₃. In yet other embodiments, three Xs in Formula IIare N and one X in Formula II is CR₃.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula III

or a pharmaceutically acceptable salt thereof, whereinwherein each R₄, R₃, (R₂)_(m), V and (L₁R₁)_(n) is defined with respectto Formula (I).

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula IV

or a pharmaceutically acceptable salt thereof, whereinwherein each R₄, R₃, (R₂)_(m), V and (L₁R¹)_(n) is defined with respectto Formula (I).

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula V

or a pharmaceutically acceptable salt thereof, wherein

each Y is independently N or CR₃ and at least one Y is N; and

wherein each R₄, R₃, (R₂)_(m), V and (L₁R₁)_(n) is defined with respectto Formula (I).

In some embodiments, each Y in Formula V is N. In other embodiments, oneY in Formula V is N the other Y in Formula V is CR₃. In yet otherembodiments, each Y in Formula V is CR₃.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula VI

or a pharmaceutically acceptable salt thereof, wherein

each Y is independently N or CR₃ and at least one Y is N; and

wherein each R₄, R₃, (R₂)_(m), V and (L₁R₁)n is defined with respect toFormula (I).

In some embodiments, each Y in Formula VI is N. In other embodiments,one Y in Formula VI is N the other Y in Formula VI is CR₃. In yet otherembodiments, each Y in Formula VI is CR₃.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula VIII

or a pharmaceutically acceptable salt thereof, wherein

each X is independently N, N-oxide or CR₃ and at least one X is N orN-oxide; and

wherein each R₄, R₃, R₂, V and L₁R₁ is defined with respect to Formula(I).

In some embodiments, each X in Formula VIII is N. In some embodiments,one X in Formula VIII is N-oxide and two Xs in Formula VIII are CR₃. Inother embodiments, one X in Formula VIII is N and two Xs in Formula VIIIare CR₃. In other embodiments, two Xs in Formula VIII are N and one X inFormula VIII is CR₃.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula IX

or a pharmaceutically acceptable salt thereof, wherein

each X is independently N, N-oxide or CR₃ and at least one X is N orN-oxide; and

wherein each R₄, R₃, R₂, V and L₁R₁ is defined with respect to Formula(I).

In some embodiments, each X in Formula IX is N. In other embodiments,one X in Formula IX is N-oxide and one X in Formula IX is CR₃. In yetother embodiments, one X in Formula IX is N and one X in Formula IX isCR₃.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula X

or a pharmaceutically acceptable salt thereof, wherein

each X is independently N, N-oxide or CR₃ and at least one X is N orN-oxide; and

wherein each R₄, R₃, R₂, V and L₁R₁ is defined with respect to Formula(I).

In some embodiments, the X in Formula X is N. In other embodiments, theX in Formula X is N-oxide.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula XI

or a pharmaceutically acceptable salt thereof, wherein

each X is independently N, N-oxide or CR₃ and at least one X is N orN-oxide; and wherein each R₄, R₃, R₂, V and L₁R₁ is defined with respectto Formula (I).

In some embodiments, the X in Formula XI is N. In other embodiments, theX in Formula XI is N-oxide.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula XII

or a pharmaceutically acceptable salt thereof, wherein

Y is N or CHR₃; and wherein each R₄, R₃, R₂, V and L₁R₁ is defined withrespect to Formula (I).

In some embodiments, the Y in Formula XII is N. In other embodiments,the Y in Formula XII is CHR₃.

In some embodiments, the compounds of Formula (I) are represented bycompounds of Formula XIII

or a pharmaceutically acceptable salt thereof, wherein

Y is N or CHR₃; and wherein each R₄, R₃, R₂, V and L₁R₁ is defined withrespect to Formula (I).

In some embodiments, each Y in Formula XIII is N. In other embodiments,one Y in Formula XIII is N the other Y in Formula XIII is CR₃. In yetother embodiments, each Y in Formula XIII is CR₃.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XV

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XVI

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XVII

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XVIII

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XIX

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XX

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXI

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXII

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXIII

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R_(I) is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXIV

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXV

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXVI

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXVII

or a pharmaceutically acceptable salt thereof, wherein

each R₄, R₃, V and L₁R₁ is defined with respect to Formula (I).

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXIX

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXIX is CH. In other embodiments, W ofFormula XXIX is N.

In some embodiments, U of Formula XXIX is C(R₁₀)₂. In other embodiments,U of Formula XXIX is NR₁₀. In yet other embodiments, U of Formula XXIXis O.

In some embodiments, R₁₀ of Formula XXIX is H. In some embodiments, R₁₀of Formula XXIX is halogen. In other embodiments, R₁₀ of Formula XXIX isfluoro. In some embodiments, R₁₀ of Formula XXIX is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XXIX is methyl or ethyl.

In some embodiments, R₁₀ of Formula XXIX is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXIX is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXIX is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXIX is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXIX is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XXIX is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXIX is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XXIX is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXIX is NCH₃. In other embodiments, Uof Formula XXIX is NCH₂CH₃.

In some embodiments, g in Formula XXIX is 0, 1, 2 or 3. In someembodiments, g in Formula XXIX is 0. In some embodiments, g in FormulaXXIX is 1. In other embodiments, g in Formula XXIX is 2. In otherembodiments, g in Formula XXIX is 3.

In some embodiments, h in Formula XXIX is 0, 1, 2 or 3. In someembodiments, h in Formula XXIX is 0. In some embodiments, h in FormulaXXIX is 1. In other embodiments, h in Formula XXIX is 2. In otherembodiments, h in Formula XXIX is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXX

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXX is CH. In other embodiments, W ofFormula XXX is N.

In some embodiments, U of Formula XXX is C(R₁₀)₂. In other embodiments,U of Formula XXX is NR₁₀. In yet other embodiments, U of Formula XXX isO.

In some embodiments, R₁₀ of Formula XXX is H. In some embodiments, R₁₀of Formula XXX is halogen. In other embodiments, R₁₀ of Formula XXX isfluoro. In some embodiments, R₁₀ of Formula XXX is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XXX is methyl or ethyl. In some embodiments,R₁₀ of Formula XXX is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXX is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula XXX is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula XXX is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula XXX isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula XXXis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula XXX is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula XXX is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula XXX is NCH₃. In other embodiments, Uof Formula XXX is NCH₂CH₃.

In some embodiments, g in Formula XXX is 0, 1, 2 or 3. In someembodiments, g in Formula XXX is 0. In some embodiments, g in FormulaXXX is 1. In other embodiments, g in Formula XXX is 2. In otherembodiments, g in Formula XXX is 3.

In some embodiments, h in Formula XXX is 0, 1, 2 or 3. In someembodiments, h in Formula XXX is 0. In some embodiments, h in FormulaXXX is 1. In other embodiments, h in Formula XXX is 2. In otherembodiments, h in Formula XXX is 3.

In some embodiments, j in Formula XXX is 0, 1, 2 or 3. In someembodiments, j in Formula XXX is 0. In some embodiments, j in FormulaXXX is 1. In other embodiments, j in Formula XXX is 2. In otherembodiments, j in Formula XXX is 3.

In some embodiments, k in Formula XXX is 0, 1, 2 or 3. In someembodiments, k in Formula XXX is 0. In some embodiments, k in FormulaXXX is 1. In other embodiments, k in Formula XXX is 2. In otherembodiments, k in Formula XXX is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXI

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or 0;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXI is CH. In other embodiments, W ofFormula XXXI is N.

In some embodiments, U of Formula XXXI is C(R₁₀)₂. In other embodiments,U of Formula XXXI is NR₁₀. In yet other embodiments, U of Formula XXXIis O.

In some embodiments, R₁₀ of Formula XXXI is H. In some embodiments, R₁₀of Formula XXXI is halogen. In other embodiments, R₁₀ of Formula XXXI isfluoro. In some embodiments, R₁₀ of Formula XXXI is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XXXI is methyl or ethyl.

In some embodiments, R₁₀ of Formula XXXI is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXI is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXXI is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXXI is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXXI is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XXXI is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXI is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XXXI is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXI is NCH₃. In other embodiments, Uof Formula XXXI is NCH₂CH₃.

In some embodiments, g in Formula XXXI is 0, 1, 2 or 3. In someembodiments, g in Formula XXXI is 0. In some embodiments, g in FormulaXXXI is 1. In other embodiments, g in Formula XXXI is 2. In otherembodiments, g in Formula XXXI is 3.

In some embodiments, h in Formula XXXI is 0, 1, 2 or 3. In someembodiments, h in Formula XXXI is 0. In some embodiments, h in FormulaXXXI is 1. In other embodiments, h in Formula XXXI is 2. In otherembodiments, h in Formula XXXI is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXII is CH. In other embodiments, Wof Formula XXXII is N.

In some embodiments, U of Formula XXXII is C(R₁₀)₂. In otherembodiments, U of Formula XXXII is NR₁₀. In yet other embodiments, U ofFormula XXXII is O.

In some embodiments, R₁₀ of Formula XXXII is H. In some embodiments, R₁₀of Formula XXXII is halogen. In other embodiments, R₁₀ of Formula XXXIIis fluoro. In some embodiments, R₁₀ of Formula XXXII is C₁₋₆alkyl. Inother embodiments, R₁₀ of Formula XXXII is methyl or ethyl. In someembodiments, R₁₀ of Formula XXXII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXXII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXXII is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXXII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XXXII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXII is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XXXII is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXII is NCH₃. In other embodiments, Uof Formula XXXII is NCH₂CH₃.

In some embodiments, g in Formula XXXII is 0, 1, 2 or 3. In someembodiments, g in Formula XXXII is 0. In some embodiments, g in FormulaXXXII is 1. In other embodiments, g in Formula XXXII is 2. In otherembodiments, g in Formula XXXII is 3.

In some embodiments, h in Formula XXXII is 0, 1, 2 or 3. In someembodiments, h in Formula XXXII is 0. In some embodiments, h in FormulaXXXII is 1. In other embodiments, h in Formula XXXII is 2. In otherembodiments, h in Formula XXXII is 3.

In some embodiments, j in Formula XXXII is 0, 1, 2 or 3. In someembodiments, j in Formula XXXII is 0. In some embodiments, j in FormulaXXXII is 1. In other embodiments, j in Formula XXXII is 2. In otherembodiments, j in Formula XXXII is 3.

In some embodiments, k in Formula XXXII is 0, 1, 2 or 3. In someembodiments, k in Formula XXXII is 0. In some embodiments, k in FormulaXXXII is 1. In other embodiments, k in Formula XXXII is 2. In otherembodiments, k in Formula XXXII is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXV

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXV is CH. In other embodiments, W ofFormula XXXV is N.

In some embodiments, U of Formula XXXV is C(R₁₀)₂. In other embodiments,U of Formula XXXV is NR₁₀. In yet other embodiments, U of Formula XXXVis O.

In some embodiments, R₁₀ of Formula XXXV is H. In some embodiments, R₁₀of Formula XXXV is halogen. In other embodiments, R₁₀ of Formula XXXV isfluoro. In some embodiments, R₁₀ of Formula XXXV is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XXXV is methyl or ethyl. In someembodiments, R₁₀ of Formula XXXV is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXV is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXXV is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXXV is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXXV is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XXXV is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXV is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XXXV is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXV is NCH₃. In other embodiments, Uof Formula XXXV is NCH₂CH₃.

In some embodiments, g in Formula XXXV is 0, 1, 2 or 3. In someembodiments, g in Formula XXXV is 0. In some embodiments, g in FormulaXXXV is 1. In other embodiments, g in Formula XXXV is 2. In otherembodiments, g in Formula XXXV is 3.

In some embodiments, h in Formula XXXV is 0, 1, 2 or 3. In someembodiments, h in Formula XXXV is 0. In some embodiments, h in FormulaXXXV is 1. In other embodiments, h in Formula XXXV is 2. In otherembodiments, h in Formula XXXV is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXVI

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXVI is CH. In other embodiments, Wof Formula XXXVI is N.

In some embodiments, U of Formula XXXVI is C(R₁₀)₂. In otherembodiments, U of Formula XXXVI is NR₁₀. In yet other embodiments, U ofFormula XXXVI is O.

In some embodiments, R₁₀ of Formula XXXVI is H. In some embodiments, R₁₀of Formula XXXVI is halogen. In other embodiments, R₁₀ of Formula XXXVIis fluoro. In some embodiments, R₁₀ of Formula XXXVI is C₁₋₆alkyl. Inother embodiments, R₁₀ of Formula XXXVI is methyl or ethyl. In someembodiments, R₁₀ of Formula XXXVI is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXVI is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXXVI is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXXVI is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXXVI is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XXXVI is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXVI is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XXXVI is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXVI is NCH₃. In other embodiments, Uof Formula XXXVI is NCH₂CH₃.

In some embodiments, g in Formula XXXVI is 0, 1, 2 or 3. In someembodiments, g in Formula XXXVI is 0. In some embodiments, g in FormulaXXXVI is 1. In other embodiments, g in Formula XXXVI is 2. In otherembodiments, g in Formula XXXVI is 3.

In some embodiments, h in Formula XXXVI is 0, 1, 2 or 3. In someembodiments, h in Formula XXXVI is 0. In some embodiments, h in FormulaXXXVI is 1. In other embodiments, h in Formula XXXVI is 2. In otherembodiments, h in Formula XXXVI is 3.

In some embodiments, j in Formula XXXVI is 0, 1, 2 or 3. In someembodiments, j in Formula XXXVI is 0. In some embodiments, j in FormulaXXXVI is 1. In other embodiments, j in Formula XXXVI is 2. In otherembodiments, j in Formula XXXVI is 3.

In some embodiments, k in Formula XXXVI is 0, 1, 2 or 3. In someembodiments, k in Formula XXXVI is 0. In some embodiments, k in FormulaXXXVI is 1. In other embodiments, k in Formula XXXVI is 2. In otherembodiments, k in Formula XXXVI is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXVII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXVII is CH. In other embodiments, Wof Formula XXXVII is N.

In some embodiments, U of Formula XXXVII is C(R₁₀)₂. In otherembodiments, U of Formula XXXVII is NR₁₀. In yet other embodiments, U ofFormula XXXVII is O.

In some embodiments, R₁₀ of Formula XXXVII is H. In some embodiments,R₁₀ of Formula XXXVII is halogen. In other embodiments, R₁₀ of FormulaXXXVII is fluoro. In some embodiments, R₁₀ of Formula XXXVII isC₁₋₆alkyl. In other embodiments, R₁₀ of Formula XXXVII is methyl orethyl. In some embodiments, R₁₀ of Formula XXXVII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXVII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXXVII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXXVII is C(R₁₀)₂, oneR₁₀ is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXXVII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments,when U of Formula XXXVII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXVII is C(R₁₀)₂,each R₁₀ is fluoro. In other embodiments, when U of Formula XXXVII isC(R₁₀)₂, one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXVII is NCH₃. In other embodiments,U of Formula XXXVII is NCH₂CH₃.

In some embodiments, g in Formula XXXVII is 0, 1, 2 or 3. In someembodiments, g in Formula XXXVII is 0. In some embodiments, g in FormulaXXXVII is 1. In other embodiments, g in Formula XXXVII is 2. In otherembodiments, g in Formula XXXVII is 3.

In some embodiments, h in Formula XXXVII is 0, 1, 2 or 3. In someembodiments, h in Formula XXXVII is 0. In some embodiments, h in FormulaXXXVII is 1. In other embodiments, h in Formula XXXVII is 2. In otherembodiments, h in Formula XXXVII is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXVIII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXVIII is CH. In other embodiments, Wof Formula XXXVIII is N.

In some embodiments, U of Formula XXXVIII is C(R₁₀)₂. In otherembodiments, U of Formula XXXVIII is NR₁₀. In yet other embodiments, Uof Formula XXXVIII is O.

In some embodiments, R₁₀ of Formula XXXVIII is H. In some embodiments,R₁₀ of Formula XXXVIII is halogen. In other embodiments, R₁₀ of FormulaXXXVIII is fluoro. In some embodiments, R₁₀ of Formula XXXVIII isC₁₋₆alkyl. In other embodiments, R₁₀ of Formula XXXVIII is methyl orethyl. In some embodiments, R₁₀ of Formula XXXVIII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXVIII is C(R₁₀)₂, each R₁₀ isH. In some embodiments, when U of Formula XXXVIII is C(R₁₀)₂, each R₁₀is methyl. In some embodiments, when U of Formula XXXVIII is C(R₁₀)₂,one R₁₀ is methyl and one R₁₀ is hydrogen. In some embodiments, when Uof Formula XXXVIII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments,when U of Formula XXXVIII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXVIII is C(R₁₀)₂,each R₁₀ is fluoro. In other embodiments, when U of Formula XXXVIII isC(R₁₀)₂, one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXVIII is NCH₃. In other embodiments,U of Formula XXXVIII is NCH₂CH₃.

In some embodiments, g in Formula XXXVIII is 0, 1, 2 or 3. In someembodiments, g in Formula XXXVIII is 0. In some embodiments, g inFormula XXXVIII is 1. In other embodiments, g in Formula XXXVIII is 2.In other embodiments, g in Formula XXXVIII is 3.

In some embodiments, h in Formula XXXVIII is 0, 1, 2 or 3. In someembodiments, h in Formula XXXVIII is 0. In some embodiments, h inFormula XXXVIII is 1. In other embodiments, h in Formula XXXVIII is 2.In other embodiments, h in Formula XXXVIII is 3.

In some embodiments, j in Formula XXXVIII is 0, 1, 2 or 3. In someembodiments, j in Formula XXXVIII is 0. In some embodiments, j inFormula XXXVIII is 1. In other embodiments, j in Formula XXXVIII is 2.In other embodiments, j in Formula XXXVIII is 3.

In some embodiments, k in Formula XXXVIII is 0, 1, 2 or 3. In someembodiments, k in Formula XXXVIII is 0. In some embodiments, k inFormula XXXVIII is 1. In other embodiments, k in Formula XXXVIII is 2.In other embodiments, k in Formula XXXVIII is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XXXIX

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XXXIX is CH. In other embodiments, Wof Formula XXXIX is N.

In some embodiments, U of Formula XXXIX is C(R₁₀)₂. In otherembodiments, U of Formula XXXIX is NR₁₀. In yet other embodiments, U ofFormula XXXIX is O.

In some embodiments, R₁₀ of Formula XXXIX is H. In some embodiments, R₁₀of Formula XXXIX is halogen. In other embodiments, R₁₀ of Formula XXXVIIis fluoro. In some embodiments, R₁₀ of Formula XXXIX is C₁₋₆alkyl. Inother embodiments, R₁₀ of Formula XXXIX is methyl or ethyl. In someembodiments, R₁₀ of Formula XXXIX is C₁₋₆alkoxide.

In some embodiments, when U of Formula XXXIX is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XXXIX is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XXXIX is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XXXIX is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XXXIX is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XXXIX is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XXXIX is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XXXIX is NCH₃. In other embodiments, Uof Formula XXXIX is NCH₂CH₃.

In some embodiments, g in Formula XXXIX is 0, 1, 2 or 3. In someembodiments, g in Formula XXXIX is 0. In some embodiments, g in FormulaXXXIX is 1. In other embodiments, g in Formula XXXIX is 2. In otherembodiments, g in Formula XXXIX is 3.

In some embodiments, h in Formula XXXIX is 0, 1, 2 or 3. In someembodiments, h in Formula XXXIX is 0. In some embodiments, h in FormulaXXXIX is 1. In other embodiments, h in Formula XXXIX is 2. In otherembodiments, h in Formula XXXIX is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XL

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XL is CH. In other embodiments, W ofFormula XL is N.

In some embodiments, U of Formula XL is C(R₁₀)₂. In other embodiments, Uof Formula XL is NR₁₀. In yet other embodiments, U of Formula XL is O.

In some embodiments, R₁₀ of Formula XL is H. In some embodiments, R₁₀ ofFormula XL is halogen. In other embodiments, R₁₀ of Formula XL isfluoro. In some embodiments, R₁₀ of Formula XL is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XL is methyl or ethyl. In some embodiments,R₁₀ of Formula XL is C₁₋₆alkoxide.

In some embodiments, when U of Formula XL is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula XL is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula XL is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula XL isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula XLis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula XL is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula XL is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula XL is NCH₃. In other embodiments, U ofFormula XL is NCH₂CH₃.

In some embodiments, g in Formula XL is 0, 1, 2 or 3. In someembodiments, g in Formula XL is 0. In some embodiments, g in Formula XLis 1. In other embodiments, g in Formula XL is 2. In other embodiments,g in Formula XL is 3.

In some embodiments, h in Formula XL is 0, 1, 2 or 3. In someembodiments, h in Formula XL is 0. In some embodiments, h in Formula XLis 1. In other embodiments, h in Formula XL is 2. In other embodiments,h in Formula XL is 3.

In some embodiments, j in Formula XL is 0, 1, 2 or 3. In someembodiments, j in Formula XL is 0. In some embodiments, j in Formula XLis 1. In other embodiments, j in Formula XL is 2. In other embodiments,j in Formula XL is 3.

In some embodiments, k in Formula XL is 0, 1, 2 or 3. In someembodiments, k in Formula XL is 0. In some embodiments, k in Formula XLis 1. In other embodiments, k in Formula XL is 2. In other embodiments,k in Formula XL is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XLI

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLI is CH. In other embodiments, W ofFormula XLI is N.

In some embodiments, U of Formula XLI is C(R₁₀)₂. In other embodiments,U of Formula XLI is NR₁₀. In yet other embodiments, U of Formula XLI isO.

In some embodiments, R₁₀ of Formula XLI is H. In some embodiments, R₁₀of Formula XLI is halogen. In other embodiments, R₁₀ of Formula XLI isfluoro. In some embodiments, R₁₀ of Formula XLI is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XLI is methyl or ethyl. In some embodiments,R₁₀ of Formula XLI is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLI is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula XLI is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula XLI is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula XLI isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula XLIis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula XLI is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula XLI is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula XLI is NCH₃. In other embodiments, Uof Formula XLI is NCH₂CH₃.

In some embodiments, g in Formula XLI is 0, 1, 2 or 3. In someembodiments, g in Formula XLI is 0. In some embodiments, g in FormulaXLI is 1. In other embodiments, g in Formula XLI is 2. In otherembodiments, g in Formula XLI is 3.

In some embodiments, h in Formula XLI is 0, 1, 2 or 3. In someembodiments, h in Formula XLI is 0. In some embodiments, h in FormulaXLI is 1. In other embodiments, h in Formula XLI is 2. In otherembodiments, h in Formula XLI is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XLII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLII is CH. In other embodiments, W ofFormula XLII is N.

In some embodiments, U of Formula XLII is C(R₁₀)₂. In other embodiments,U of Formula XLII is NR₁₀. In yet other embodiments, U of Formula XLIIis O.

In some embodiments, R₁₀ of Formula XLII is H. In some embodiments, R₁₀of Formula XLII is halogen. In other embodiments, R₁₀ of Formula XLII isfluoro. In some embodiments, R₁₀ of Formula XLII is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XLII is methyl or ethyl. In someembodiments, R₁₀ of Formula XLII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLII is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XLII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLII is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XLII is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLII is NCH₃. In other embodiments, Uof Formula XLII is NCH₂CH₃.

In some embodiments, g in Formula XLII is 0, 1, 2 or 3. In someembodiments, g in Formula XLII is 0. In some embodiments, g in FormulaXLII is 1. In other embodiments, g in Formula XLII is 2. In otherembodiments, g in Formula XLII is 3.

In some embodiments, h in Formula XLII is 0, 1, 2 or 3. In someembodiments, h in Formula XLII is 0. In some embodiments, h in FormulaXLII is 1. In other embodiments, h in Formula XLII is 2. In otherembodiments, h in Formula XLII is 3.

In some embodiments, j in Formula XLII is 0, 1, 2 or 3. In someembodiments, j in Formula XLII is 0. In some embodiments, j in FormulaXLII is 1. In other embodiments, j in Formula XLII is 2. In otherembodiments, j in Formula XLII is 3.

In some embodiments, k in Formula XLII is 0, 1, 2 or 3. In someembodiments, k in Formula XLII is 0. In some embodiments, k in FormulaXLII is 1. In other embodiments, k in Formula XLII is 2. In otherembodiments, k in Formula XLII is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XLIII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g and h is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLIII is CH. In other embodiments, Wof Formula XLIII is N.

In some embodiments, U of Formula XLIII is C(R₁₀)₂. In otherembodiments, U of Formula XLIII is NR₁₀. In yet other embodiments, U ofFormula XLIII is O.

In some embodiments, R₁₀ of Formula XLIII is H. In some embodiments, R₁₀of Formula XLIII is halogen. In other embodiments, R₁₀ of Formula XLIIIis fluoro. In some embodiments, R₁₀ of Formula XLI is C₁₋₆alkyl. Inother embodiments, R₁₀ of Formula XLIII is methyl or ethyl. In someembodiments, R₁₀ of Formula XLIII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLIII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLIII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLIII is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLIII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XLIII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLIII is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XLIII is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLIII is NCH₃. In other embodiments, Uof Formula XLIII is NCH₂CH₃.

In some embodiments, g in Formula XLIII is 0, 1, 2 or 3. In someembodiments, g in Formula XLIII is 0. In some embodiments, g in FormulaXLIII is 1. In other embodiments, g in Formula XLIII is 2. In otherembodiments, g in Formula XLIII is 3.

In some embodiments, h in Formula XLIII is 0, 1, 2 or 3. In someembodiments, h in Formula XLIII is 0. In some embodiments, h in FormulaXLIII is 1. In other embodiments, h in Formula XLIII is 2. In otherembodiments, h in Formula XLIII is 3.

In other embodiments, the compounds of Formula (I) are represented bycompounds of Formula XLIV

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide;

each g, h, j and k is independently 0, 1, 2 or 3; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLIV is CH. In other embodiments, W ofFormula XLIV is N.

In some embodiments, U of Formula XLIV is C(R₁₀)₂. In other embodiments,U of Formula XLIV is NR₁₀. In yet other embodiments, U of Formula XLIVis O.

In some embodiments, R₁₀ of Formula XLIV is H. In some embodiments, R₁₀of Formula XLIV is halogen. In other embodiments, R₁₀ of Formula XLIV isfluoro. In some embodiments, R₁₀ of Formula XLIV is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XLIV is methyl or ethyl.

In some embodiments, R₁₀ of Formula XLIV is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLIV is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLIV is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLIV is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLIV is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XLIV is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLIV is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XLIV is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLIV is NCH₃. In other embodiments, Uof Formula XLIV is NCH₂CH₃.

In some embodiments, g in Formula XLIV is 0, 1, 2 or 3. In someembodiments, g in Formula XLIV is 0. In some embodiments, g in FormulaXLIV is 1. In other embodiments, g in Formula XLIV is 2. In otherembodiments, g in Formula XLIV is 3.

In some embodiments, h in Formula XLIV is 0, 1, 2 or 3. In someembodiments, h in Formula XLIV is 0. In some embodiments, h in FormulaXLIV is 1. In other embodiments, h in Formula XLIV is 2. In otherembodiments, h in Formula XLIV is 3.

In some embodiments, j in Formula XLIV is 0, 1, 2 or 3. In someembodiments, j in Formula XLIV is 0. In some embodiments, j in FormulaXLIV is 1. In other embodiments, j in Formula XLIV is 2. In otherembodiments, j in Formula XLIV is 3.

In some embodiments, k in Formula XLIV is 0, 1, 2 or 3. In someembodiments, k in Formula XLIV is 0. In some embodiments, k in FormulaXLIV is 1. In other embodiments, k in Formula XLIV is 2. In otherembodiments, k in Formula XLIV is 3.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula XLV

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLV is CH. In other embodiments, W ofFormula XLV is N.

In some embodiments, U of Formula XLV is C(R₁₀)₂. In other embodiments,U of Formula XLV is NR₁₀. In yet other embodiments, U of Formula XLV isO.

In some embodiments, R₁₀ of Formula XLV is H. In some embodiments, R₁₀of Formula XLV is halogen. In other embodiments, R₁₀ of Formula XLV isfluoro. In some embodiments, R₁₀ of Formula XLV is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XLV is methyl or ethyl. In some embodiments,R₁₀ of Formula XLV is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLV is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula XLV is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula XLV is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula XLV isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula XLVis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula XLV is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula XLV is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula XLV is NCH₃. In other embodiments, Uof Formula XLV is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula XLVI

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLVI is CH. In other embodiments, W ofFormula XLVI is N.

In some embodiments, U of Formula XLVI is C(R₁₀)₂. In other embodiments,U of Formula XLVI is NR₁₀. In yet other embodiments, U of Formula XLVIis O.

In some embodiments, R₁₀ of Formula XLVI is H. In some embodiments, R₁₀of Formula XLVI is halogen. In other embodiments, R₁₀ of Formula XLVI isfluoro. In some embodiments, R₁₀ of Formula XLVI is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XLVI is methyl or ethyl.

In some embodiments, R₁₀ of Formula XLV is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLVI is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLVI is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLVI is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLVI is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XLVI is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLVI is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XLVI is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLVI is NCH₃. In other embodiments, Uof Formula XLVI is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula XLVII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLVII is CH. In other embodiments, Wof Formula XLVII is N.

In some embodiments, U of Formula XLVII is C(R₁₀)₂. In otherembodiments, U of Formula XLVII is NR₁₀. In yet other embodiments, U ofFormula XLVII is O.

In some embodiments, R₁₀ of Formula XLVII is H. In some embodiments, R₁₀of Formula XLVII is halogen. In other embodiments, R₁₀ of Formula XLVIIis fluoro. In some embodiments, R₁₀ of Formula XLVII is C₁₋₆alkyl. Inother embodiments, R₁₀ of Formula XLVII is methyl or ethyl.

In some embodiments, R₁₀ of Formula XLVII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLVII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLVII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLVII is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLVII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XLVII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLVII is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XLVII is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLVII is NCH₃. In other embodiments, Uof Formula XLVII is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula XLVIII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLVIII is CH. In other embodiments, Wof Formula XLVIII is N.

In some embodiments, U of Formula XLVIII is C(R₁₀)₂. In otherembodiments, U of Formula XLVIII is NR₁₀. In yet other embodiments, U ofFormula XLVIII is O.

In some embodiments, R₁₀ of Formula XLVIII is H. In some embodiments,R₁₀ of Formula XLVIII is halogen. In other embodiments, R₁₀ of FormulaXLVIII is fluoro. In some embodiments, R₁₀ of Formula XLVIII isC₁₋₆alkyl. In other embodiments, R₁₀ of Formula XLVIII is methyl orethyl. In some embodiments, R₁₀ of Formula XLVIII is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLVIII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLVIII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLVIII is C(R₁₀)₂, oneR₁₀ is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLVIII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments,when U of Formula XLVIII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLVIII is C(R₁₀)₂,each R₁₀ is fluoro. In other embodiments, when U of Formula XLVIII isC(R₁₀)₂, one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLVIII is NCH₃. In other embodiments,U of Formula XLVIII is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula XLIX

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula XLIX is CH. In other embodiments, W ofFormula XLIX is N.

In some embodiments, U of Formula XLIX is C(R₁₀)₂. In other embodiments,U of Formula XLIX is NR₁₀. In yet other embodiments, U of Formula XLIXis O.

In some embodiments, R₁₀ of Formula XLIX is H. In some embodiments, R₁₀of Formula XLIX is halogen. In other embodiments, R₁₀ of Formula XLIX isfluoro. In some embodiments, R₁₀ of Formula XLIX is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula XLIX is methyl or ethyl.

In some embodiments, R₁₀ of Formula XLIX is C₁₋₆alkoxide.

In some embodiments, when U of Formula XLIX is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula XLIX is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula XLIX is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula XLIX is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula XLIX is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula XLIX is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula XLIX is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula XLIX is NCH₃. In other embodiments, Uof Formula XLIX is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula L

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula L is CH. In other embodiments, W ofFormula XLIX is N.

In some embodiments, U of Formula L is C(R₁₀)₂. In other embodiments, Uof Formula L is NR₁₀. In yet other embodiments, U of Formula L is O.

In some embodiments, R₁₀ of Formula L is H. In some embodiments, R₁₀ ofFormula L is halogen. In other embodiments, R₁₀ of Formula L is fluoro.In some embodiments, R₁₀ of Formula L is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula L is methyl or ethyl. In some embodiments,R₁₀ of Formula L is C₁₋₆alkoxide.

In some embodiments, when U of Formula L is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula L is C(R₁₀)₂, each R₁₀ is methyl. Insome embodiments, when U of Formula L is C(R₁₀)₂, one R₁₀ is methyl andone R₁₀ is hydrogen. In some embodiments, when U of Formula L isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula Lis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula L is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula L is C(R₁₀)₂, one R₁₀ is fluoro andone R₁₀ is hydrogen.

In some embodiments, U of Formula L is NCH₃. In other embodiments, U ofFormula L is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LI

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula LI is CH. In other embodiments, W ofFormula LI is N.

In some embodiments, U of Formula LI is C(R₁₀)₂. In other embodiments, Uof Formula LI is NR₁₀. In yet other embodiments, U of Formula LI is O.

In some embodiments, R₁₀ of Formula LI is H. In some embodiments, R₁₀ ofFormula LI is halogen. In other embodiments, R₁₀ of Formula LI isfluoro. In some embodiments, R₁₀ of Formula LI is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula LI is methyl or ethyl. In some embodiments,R₁₀ of Formula LI is C₁₋₆alkoxide.

In some embodiments, when U of Formula LI is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula LI is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula LI is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula LI isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula LIis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula LI is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula LI is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula LI is NCH₃. In other embodiments, U ofFormula LI is NCH₂CH₃.

The following are particularly preferred

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula LII is CH. In other embodiments, W ofFormula LII is N.

In some embodiments, U of Formula LII is C(R₁₀)₂. In other embodiments,U of Formula LII is NR₁₀. In yet other embodiments, U of Formula LII isO.

In some embodiments, R₁₀ of Formula LII is H. In some embodiments, R₁₀of Formula LII is halogen. In other embodiments, R₁₀ of Formula LII isfluoro. In some embodiments, R₁₀ of Formula LII is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula LII is methyl or ethyl. In some embodiments,R₁₀ of Formula LII is C₁₋₆alkoxide.

In some embodiments, when U of Formula LII is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula LII is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula LII is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula LII isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula LIIis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula LII is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula LII is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula LII is NCH₃. In other embodiments, Uof Formula LII is NCH₂CH₃.

The following are particularly preferred

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LIII

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula LIII is CH. In other embodiments, W ofFormula LIII is N.

In some embodiments, U of Formula LIII is C(R₁₀)₂. In other embodiments,U of Formula LIII is NR₁₀. In yet other embodiments, U of Formula LIIIis O.

In some embodiments, R₁₀ of Formula LIII is H. In some embodiments, R₁₀of Formula LIII is halogen. In other embodiments, R₁₀ of Formula LIII isfluoro. In some embodiments, R₁₀ of Formula LIII is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula LIII is methyl or ethyl. In someembodiments, R₁₀ of Formula LIII is C₁₋₆alkoxide.

In some embodiments, when U of Formula LIII is C(R₁₀)₂, each R₁₀ is H.In some embodiments, when U of Formula LIII is C(R₁₀)₂, each R₁₀ ismethyl. In some embodiments, when U of Formula LIII is C(R₁₀)₂, one R₁₀is methyl and one R₁₀ is hydrogen. In some embodiments, when U ofFormula LIII is C(R₁₀)₂, each R₁₀ is halogen. In some embodiments, whenU of Formula LIII is C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ ishydrogen. In other embodiments, when U of Formula LIII is C(R₁₀)₂, eachR₁₀ is fluoro. In other embodiments, when U of Formula LIII is C(R₁₀)₂,one R₁₀ is fluoro and one R₁₀ is hydrogen.

In some embodiments, U of Formula LIII is NCH₃. In other embodiments, Uof Formula LIII is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LIV

or a pharmaceutically acceptable salt thereof, wherein

W is CH or N;

U is C(R₁₀)₂, NR₁₀, or O;

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, W of Formula LIV is CH. In other embodiments, W ofFormula LIV is N.

In some embodiments, U of Formula LIV is C(R₁₀)₂. In other embodiments,U of Formula LIV is NR₁₀. In yet other embodiments, U of Formula LIV isO.

In some embodiments, R₁₀ of Formula LIV is H. In some embodiments, R₁₀of Formula LIV is halogen. In other embodiments, R₁₀ of Formula LIV isfluoro. In some embodiments, R₁₀ of Formula LIV is C₁₋₆alkyl. In otherembodiments, R₁₀ of Formula LIV is methyl or ethyl. In some embodiments,R₁₀ of Formula LIV is C₁₋₆alkoxide.

In some embodiments, when U of Formula LIV is C(R₁₀)₂, each R₁₀ is H. Insome embodiments, when U of Formula LIV is C(R₁₀)₂, each R₁₀ is methyl.In some embodiments, when U of Formula LIV is C(R₁₀)₂, one R₁₀ is methyland one R₁₀ is hydrogen. In some embodiments, when U of Formula LIV isC(R₁₀)₂, each R₁₀ is halogen. In some embodiments, when U of Formula LIVis C(R₁₀)₂, one R₁₀ is halogen and one R₁₀ is hydrogen. In otherembodiments, when U of Formula LIV is C(R₁₀)₂, each R₁₀ is fluoro. Inother embodiments, when U of Formula LIV is C(R₁₀)₂, one R₁₀ is fluoroand one R₁₀ is hydrogen.

In some embodiments, U of Formula LIV is NCH₃. In other embodiments, Uof Formula LIV is NCH₂CH₃.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LVII

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LVII is H. In some embodiments, R₁₀of Formula LVII is C₁₋₆alkyl. In other embodiments, R₁₀ of Formula LVIIis methyl. In other embodiments, R₁₀ of Formula LI is ethyl.

Particularly preferred compounds are

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LVIII

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LVIII is H. In some embodiments, R₁₀of Formula LVIII is C₁₋₆alkyl. In other embodiments, R₁₀ of FormulaLVIII is methyl. In other embodiments, R₁₀ of Formula LVIII is ethyl.

Particularly preferred compounds are

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LIX

or a pharmaceutically acceptable salt thereof, whereinR₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LIX is H. In some embodiments, R₁₀of Formula LIX is C₁₋₆alkyl. In other embodiments, R₁₀ of Formula LIX ismethyl. In other embodiments, R₁₀ of Formula LIX is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LX

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LX is H. In some embodiments, R₁₀ ofFormula LX is C₁₋₆alkyl. In other embodiments, R₁₀ of Formula LX ismethyl. In other embodiments, R₁₀ of Formula LX is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LXIII

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LXIII is H. In some embodiments, R₁₀of Formula LXIII is C₁₋₆alkyl. In other embodiments, R₁₀ of FormulaLXIII is methyl. In other embodiments, R₁₀ of Formula LXIII is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LXIV

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LXIV is H. In some embodiments, R₁₀of Formula LXIV is C₁₋₆alkyl. In other embodiments, R₁₀ of Formula LXIVis methyl. In other embodiments, R₁₀ of Formula LXIV is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LXV

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; andeach R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LXV is H. In some embodiments, R₁₀of Formula LXV is C₁₋₆alkyl. In other embodiments, R₁₀ of Formula LXV ismethyl. In other embodiments, R₁₀ of Formula LXV is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LXVI

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LXVI is H. In some embodiments, R₁₀of Formula LXVI is C₁₋₆alkyl. In other embodiments, R₁₀ of Formula LXVIis methyl. In other embodiments, R₁₀ of Formula LXVI is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula LXVII

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LXVII is H. In some embodiments, R₁₀of Formula LXVII is C₁₋₆alkyl. In other embodiments, R₁₀ of FormulaLXVII is methyl. In other embodiments, R₁₀ of Formula LXVII is ethyl.

In yet other embodiments, the compounds of Formula (I) are representedby compounds of Formula c

or a pharmaceutically acceptable salt thereof, wherein

R₁₀ is H, halogen (preferably fluoro), C₁₋₆alkyl, or C₁₋₆alkoxide; and

each R₄, R₃, V and L₁ is defined with respect to Formula (I).

In some embodiments, R₁₀ of Formula LXVIII is H. In some embodiments,R₁₀ of Formula LXVIII is C₁₋₆alkyl. In other embodiments, R₁₀ of FormulaLXVIII is methyl. In other embodiments, R₁₀ of Formula LXVIII is ethyl.

In yet further embodiments, the compounds of Formula (I) are:

-   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   N-(5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;-   N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;-   4-(3-Cyclobutyl-2,6-dimethylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(3-Cyclobutyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(3-Cyclobutyl-2,6-dimethylthieno[2,3-d]imidazol-5-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   4-(3-Cyclopentyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;-   N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;-   2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;-   N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;-   4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(1-ethylpiperidin-4-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;-   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   N-[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   2-[2-[2-[[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;-   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   2-[2-[2-[[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;-   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;-   2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;-   4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   N-(5-(2,6-Diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;-   4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methoxypiperidin-1-yl)pyridin-2-yl]pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine;-   4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine;-   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;-   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;-   4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(7-Cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;-   4-(4-Cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxido-7-propan-2-ylthieno[3,2-b]pyridin-4-ium-2-yl)pyrimidin-2-amine;-   2-[5-Fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro    [3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   6-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;-   (4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(2-((5-(6-Ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;-   2-(2-((5-(4-Ethylpiperazine-1-carbonyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   6-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one;-   2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one;

or a pharmaceutically acceptable salt thereof.

In yet further embodiments, the compounds of Formula (I) are:

-   N-[5-[[4-(2,2-Difluoroethyl)piperazin-1-yl]methyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)    pyrimidin-2-amine;-   1-[[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]    imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl]-N,N-dimethylpyrrolidine-3-carboxamide;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-pyridin-2-ylpyrimidin-2-amine;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)    pyridin-2-yl]pyrimidin-2-amine;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethyl-6,6-difluoro-1,4-diazepan-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazin-1-yl]pyridin-2-yl]pyrimidin-2-amine;-   N-[5-(5,5-Difluoro-7-methyl-2,7-diazaspiro[3.4]octan-2-yl)pyridin-2-yl]-4-(2,6-dimethyl-3-propan-2-ylthieno[2,3-d]    imidazol-5-yl)-5-fluoropyrimidin-2-amine;-   (6-Dthyl-2,6-diazaspiro[3.3]heptan-2-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]    imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone;-   N-[5-[3-(Dimethylamino)    azetidin-1-yl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;-   N-[5-[3-(Dimethylamino)    pyrrolidin-1-yl]pyridin-2-yl]-4-(2,6-dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine;-   N-[5-(6-ethyl-3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;-   1-[6-[[4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino]pyridin-3-yl]-4-methylpiperazin-2-one;-   2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(2-((5-(5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-(methyl-d3)piperidin-4-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(2-((5-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3-methyl-5-(methyl-d3)thieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;-   2-(2-((5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(2-((5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]    pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((6-(1-methylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)    pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   2-(5-Fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno    [3,2-c]pyridin-4(5H)-one;-   7-Isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)    pyridine-2-yl)amino) pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one;-   7-Isopropyl-5-methyl-2-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno    [3,2-c]pyridin-4(5H)-one;-   4-(6-((5-Fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-yl)amino)    pyridin-3-yl)-1-methylpiperidine 1-oxide;-   5-Fluoro-4-(3-isopropyl-2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine;-   4-(3-Cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;-   2-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]    pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol;-   1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]    pyrazol-3-yl)ethan-1-one;-   1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]    pyrazol-3-yl)ethan-1-ol;-   N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2-methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]    pyrazol-5-yl)pyrimidin-2-amine;-   4-(1,6-dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)    pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   N-(5-Fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;-   5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;-   tert-Butyl    3-(2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazin-7-yl)azetidine-1-carboxylate;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one;-   5-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine;-   N-(5-(2-Ethyl-2-azaspiro    [3.3]heptan-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1-yl)    pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]pyrimidin-2-amine;-   5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylmorpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine;-   N-[5-[1-(4-Ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)    pyrimidin-2-amine;-   3-[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one;-   ((8aS)-6-(6-((5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)    pyrimidin-2-yl)amino)pyridin-3-yl)-2-methylhexahydropyrrolo    [1,2-a]pyrazin-3(4H)-one;-   4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1-yl)    pyridin-2-yl]-5-fluoropyrimidin-2-amine;-   4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)    pyridin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;-   N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-propan-2-yl-3-(trifluoromethyl)    thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine;-   2-(2-((5-(4-Ethylpiperazin-1-yl)    pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropylthieno[3,2-b]pyridine-3-carbonitrile;-   5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propan-2-ylthieno[3,2-c]pyridin-2-yl)    pyrimidin-2-amine;-   N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;-   5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)    pyrimidin-2-amine (isomer 1);-   5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine    (isomer 2);-   4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-methoxy-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;-   N-(5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)    pyrimidin-2-amine;-   N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)    pyridin-2-yl)-5-fluoro-4-(3-isopropyl-3H-thieno[2,3-d]    imidazol-5-yl)pyrimidin-2-amine;-   5-Chloro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;-   2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]    pyridine 5-oxide;

or a pharmaceutically acceptable salt thereof.

It will be apparent that the compounds of Formula I, including allsubgenera described herein, may have multiple stereogenic centers. As aresult, there exist multiple stereoisomers (enantiomers anddiastereomers) of the compounds of Formula I (and subgenera describedherein). The present disclosure contemplates and encompasses eachstereoisomer of any compound of Formula I (and subgenera describedherein), as well as mixtures of said stereoisomers.

Pharmaceutically acceptable salts and solvates of the compounds ofFormula I (including all subgenera described herein) are also within thescope of the disclosure.

Isotopic variants of the compounds of Formula I (including all subgeneradescribed herein) are also contemplated by the present disclosure.

Pharmaceutical Compositions and Methods of Administration

In some embodiments, the disclosure is directed to pharmaceuticalcompositions comprising compounds of Formula I, or a pharmaceuticallyacceptable salt or solvate thereof.

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentdisclosure as the active ingredient, or a pharmaceutically acceptablesalt, ester, prodrug, solvate, hydrate or derivative thereof. Wheredesired, the pharmaceutical compositions contain pharmaceuticallyacceptable salt and/or coordination complex thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the one or more compounds of the invention and other agent(s) may bemixed into a preparation or both components may be formulated intoseparate preparations to use them in combination separately or at thesame time.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%,0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%,0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%,0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number inthe range defined by and including any two numbers above) w/w, w/v orv/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%,12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%,7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%,4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%,1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%,0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or0.0001% (or a number in the range defined by and including any twonumbers above) w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in therange defined by and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range definedby and including any two numbers above).

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that may be used. Anexemplary dosage is 10 to 30 mg per day. The exact dosage will dependupon the route of administration, the form in which the compound isadministered, the subject to be treated, the body weight of the subjectto be treated, and the preference and experience of the attendingphysician.

A pharmaceutical composition of the invention typically contains anactive ingredient (i.e., a compound of the disclosure) of the presentinvention or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, including but not limited to inert solid diluents and fillers,diluents, sterile aqueous solution and various organic solvents,permeation enhancers, solubilizers and adjuvants.

Described below are non-limiting exemplary pharmaceutical compositionsand methods for preparing the same.

Pharmaceutical Compositions for Oral Administration.

In some embodiments, the invention provides a pharmaceutical compositionfor oral administration containing a compound of the invention, and apharmaceutical excipient suitable for oral administration.

In some embodiments, the invention provides a solid pharmaceuticalcomposition for oral administration containing: (i) an effective amountof a compound of the invention; optionally (ii) an effective amount of asecond agent; and (iii) a pharmaceutical excipient suitable for oraladministration. In some embodiments, the composition further contains:(iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition may be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions of the invention suitable for oral administration can bepresented as discrete dosage forms, such as capsules, cachets, ortablets, or liquids or aerosol sprays each containing a predeterminedamount of an active ingredient as a powder or in granules, a solution,or a suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Such dosage forms can beprepared by any of the methods of pharmacy, but all methods include thestep of bringing the active ingredient into association with thecarrier, which constitutes one or more necessary ingredients. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product intothe desired presentation. For example, a tablet can be prepared bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets can be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such aspowder or granules, optionally mixed with an excipient such as, but notlimited to, a binder, a lubricant, an inert diluent, and/or a surfaceactive or dispersing agent. Molded tablets can be made by molding in asuitable machine a mixture of the powdered compound moistened with aninert liquid diluent.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising an active ingredient, since water canfacilitate the degradation of some compounds. For example, water may beadded (e.g., 5%) in the pharmaceutical arts as a means of simulatinglong-term storage in order to determine characteristics such asshelf-life or the stability of formulations over time. Anhydrouspharmaceutical compositions and dosage forms of the invention can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. Pharmaceutical compositions anddosage forms of the invention which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition may be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions maybe packaged using materials known to prevent exposure to water such thatthey can be included in suitable formulary kits. Examples of suitablepackaging include, but are not limited to, hermetically sealed foils,plastic or the like, unit dose containers, blister packs, and strippacks.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the compositions for an oral dosage form, any of the usualpharmaceutical media can be employed as carriers, such as, for example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations(such as suspensions, solutions, and elixirs) or aerosols; or carrierssuch as starches, sugars, micro-crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents canbe used in the case of oral solid preparations, in some embodimentswithout employing the use of lactose. For example, suitable carriersinclude powders, capsules, and tablets, with the solid oralpreparations. If desired, tablets can be coated by standard aqueous ornonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention toprovide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant may produce tablets which maydisintegrate in the bottle. Too little may be insufficient fordisintegration to occur and may thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) maybe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used may vary based upon the type of formulationand mode of administration, and may be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, maybe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms of theinvention include, but are not limited to, agar-agar, alginic acid,calcium carbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifso desired, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

Surfactant which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to,hydrophilic surfactants, lipophilic surfactants, and mixtures thereof.That is, a mixture of hydrophilic surfactants may be employed, a mixtureof lipophilic surfactants may be employed, or a mixture of at least onehydrophilic surfactant and at least one lipophilic surfactant may beemployed.

A suitable hydrophilic surfactant may generally have an HLB value of atleast 10, while suitable lipophilic surfactants may generally have anHLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions.

Hydrophilic surfactants are generally considered to be those compoundshaving an HLB value greater than about 10, as well as anionic, cationic,or zwitterionic compounds for which the HLB scale is not generallyapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants arecompounds having an HLB value equal to or less than about 10. However,HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical and cosmetic emulsions.

Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof, lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acyl lactylates; mono- and di-acetylatedtartaric acid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants may be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-ionic surfactants may include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylenesterols, derivatives, and analogues thereof; polyoxyethylated vitaminsand derivatives thereof, polyoxyethylene-polyoxypropylene blockcopolymers; and mixtures thereof, polyethylene glycol sorbitan fattyacid esters and hydrophilic transesterification products of a polyolwith at least one member of the group consisting of triglycerides,vegetable oils, and hydrogenated vegetable oils. The polyol may beglycerol, ethylene glycol, polyethylene glycol, sorbitol, propyleneglycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrosemono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of the group consisting of glycerides, vegetable oils,hydrogenated vegetable oils, fatty acids and sterols; oil-solublevitamins/vitamin derivatives; and mixtures thereof. Within this group,preferred lipophilic surfactants include glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of the group consisting of vegetable oils, hydrogenated vegetableoils, and triglycerides.

In one embodiment, the composition may include a solubilizer to ensuregood solubilization and/or dissolution of the compound of the presentinvention and to minimize precipitation of the compound of the presentinvention. This can be especially important for compositions fornon-oral use, e.g., compositions for injection. A solubilizer may alsobe added to increase the solubility of the hydrophilic drug and/or othercomponents, such as surfactants, or to maintain the composition as astable or homogeneous solution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, F-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, F-caprolactone and isomers thereof, S-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof, and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. Particularlypreferred solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included is not particularlylimited. The amount of a given solubilizer may be limited to abioacceptable amount, which may be readily determined by one of skill inthe art. In some circumstances, it may be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the composition to a subjectusing conventional techniques, such as distillation or evaporation.Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100% o, or up to about 200%>by weight, based on the combinedweight of the drug, and other excipients. If desired, very small amountsof solubilizer may also be used, such as 5%>, 2%>, 1%) or even less.Typically, the solubilizer may be present in an amount of about 1%>toabout 100%, more typically about 5%>to about 25%>by weight.

The composition can further include one or more pharmaceuticallyacceptable additives and excipients. Such additives and excipientsinclude, without limitation, detackifiers, anti-foaming agents,buffering agents, polymers, antioxidants, preservatives, chelatingagents, viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof.

In addition, an acid or a base may be incorporated into the compositionto facilitate processing, to enhance stability, or for other reasons.Examples of pharmaceutically acceptable bases include amino acids, aminoacid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Example may include,but not limited to, sodium, potassium, lithium, magnesium, calcium andammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Pharmaceutical Compositions for Injection.

In some embodiments, the invention provides a pharmaceutical compositionfor injection containing a compound of the present invention and apharmaceutical excipient suitable for injection. Components and amountsof agents in the compositions are as described herein.

The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils may also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof the present invention in the required amount in the appropriatesolvent with various other ingredients as enumerated above, as required,followed by filtered sterilization. Generally, dispersions are preparedby incorporating the various sterilized active ingredients into asterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions,certain desirable methods of preparation are vacuum-drying andfreeze-drying techniques which yield a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Pharmaceutical Compositions for Topical (e.g. Transdermal) Delivery.

In some embodiments, the invention provides a pharmaceutical compositionfor transdermal delivery containing a compound of the present inventionand a pharmaceutical excipient suitable for transdermal delivery.

Compositions of the present invention can be formulated intopreparations in solid, semisolid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, creams,lotions, suspensions, foams, powders, slurries, ointments, solutions,oils, pastes, suppositories, sprays, emulsions, saline solutions,dimethylsulfoxide (DMSO)-based solutions. In general, carriers withhigher densities are capable of providing an area with a prolongedexposure to the active ingredients. In contrast, a solution formulationmay provide more immediate exposure of the active ingredient to thechosen area.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation.

Examples of such carriers and excipients include, but are not limitedto, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols(e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g.,isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerolmonolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides,alkanes, alkanols, water, calcium carbonate, calcium phosphate, varioussugars, starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

Another exemplary formulation for use in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of a compound of the present invention in controlled amounts,either with or without another agent.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Pharmaceutical Compositions for Inhalation.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

Other Pharmaceutical Compositions.

Pharmaceutical compositions may also be prepared from compositionsdescribed herein and one or more pharmaceutically acceptable excipientssuitable for sublingual, buccal, rectal, intraosseous, intraocular,intranasal, epidural, or intraspinal administration. Preparations forsuch pharmaceutical compositions are well-known in the art. See, e.g.,Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

Administration of the compounds or pharmaceutical composition of thepresent invention can be effected by any method that enables delivery ofthe compounds to the site of action. These methods include oral routes,intraduodenal routes, parenteral injection (including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion), topical (e.g. transdermal application),rectal administration, via local delivery by catheter or stent orthrough inhalation. Compounds can also be administered intraadiposallyor intrathecally.

The amount of the compound administered will be dependent on the subjectbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose.

Typically, such administration will be by injection, e.g., intravenousinjection, in order to introduce the agent quickly. However, otherroutes may be used as appropriate. A single dose of a compound of theinvention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compositions of the invention may also be delivered via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer. Such a method of administrationmay, for example, aid in the prevention or amelioration of restenosisfollowing procedures such as balloon angioplasty. Without being bound bytheory, compounds of the invention may slow or inhibit the migration andproliferation of smooth muscle cells in the arterial wall whichcontribute to restenosis. A compound of the invention may beadministered, for example, by local delivery from the struts of a stent,from a stent graft, from grafts, or from the cover or sheath of a stent.In some embodiments, a compound of the invention is admixed with amatrix. Such a matrix may be a polymeric matrix, and may serve to bondthe compound to the stent. Polymeric matrices suitable for such use,include, for example, lactone-based polyesters or copolyesters such aspolylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides,polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester)copolymers (e.g. PEO-PLLA); polydimethylsiloxane,poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g.polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone),fluorinated polymers such as polytetrafluoroethylene and celluloseesters. Suitable matrices may be nondegrading or may degrade with time,releasing the compound or compounds. Compounds of the invention may beapplied to the surface of the stent by various methods such as dip/spincoating, spray coating, dip-coating, and/or brush-coating. The compoundsmay be applied in a solvent and the solvent may be allowed to evaporate,thus forming a layer of compound onto the stent. Alternatively, thecompound may be located in the body of the stent or graft, for examplein microchannels or micropores. When implanted, the compound diffusesout of the body of the stent to contact the arterial wall. Such stentsmay be prepared by dipping a stent manufactured to contain suchmicropores or microchannels into a solution of the compound of theinvention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent may be removed via an additionalbrief solvent wash. In yet other embodiments, compounds of the inventionmay be covalently linked to a stent or graft. A covalent linker may beused which degrades in vivo, leading to the release of the compound ofthe invention. Any bio-labile linkage may be used for such a purpose,such as ester, amide or anhydride linkages. Compounds of the inventionmay additionally be administered intravascularly from a balloon usedduring angioplasty. Extravascular administration of the compounds viathe pericard or via advential application of formulations of theinvention may also be performed to decrease restenosis.

A variety of stent devices which may be used as described are disclosed,for example, in the following references, all of which are herebyincorporated by reference: U.S. Pat. Nos. 5,451,233; 5,040,548;5,061,273; 5,496,346; 5,292,331; 5,674,278; 3,657,744; 4,739,762;5,195,984; 5,292,331; U.S. Pat. Nos. 5,674,278; 5,879,382; 6,344,053.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compound in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Methods of Use

The method typically comprises administering to a subject atherapeutically effective amount of a compound of the invention. Thetherapeutically effective amount of the subject combination of compoundsmay vary depending upon the intended application (in vitro or in vivo),or the subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofproliferation or downregulation of activity of a target protein. Thespecific dose will vary depending on the particular compounds chosen,the dosing regimen to be followed, whether it is administered incombination with other compounds, timing of administration, the tissueto which it is administered, and the physical delivery system in whichit is carried.

As used herein, the term “IC₅₀” refers to the half maximal inhibitoryconcentration of an inhibitor in inhibiting biological or biochemicalfunction. This quantitative measure indicates how much of a particularinhibitor is needed to inhibit a given biological process (or componentof a process, i.e. an enzyme, cell, cell receptor or microorganism) byhalf. In other words, it is the half maximal (50%) inhibitoryconcentration (IC) of a substance (50% IC, or IC50). EC50 refers to theplasma concentration required for obtaining 50%>of a maximum effect invivo.

In some embodiments, the subject methods utilize a CDK inhibitor with anIC50 value of about or less than a predetermined value, as ascertainedin an in vitro assay. In some embodiments, the CDK inhibitor inhibitsCDK a with an IC50 value of about 1 nM or less, 2 nM or less, 5 nM orless, 7 nM or less, 10 nM or less, 20 nM or less, 30 nM or less, 40 nMor less, 50 nM or less, 60 nM or less, 70 nM or less, 80 nM or less, 90nM or less, 100 nM or less, 120 nM or less, 140 nM or less, 150 nM orless, 160 nM or less, 170 nM or less, 180 nM or less, 190 nM or less,200 nM or less, 225 nM or less, 250 nM or less, 275 nM or less, 300 nMor less, 325 nM or less, 350 nM or less, 375 nM or less, 400 nM or less,425 nM or less, 450 nM or less, 475 nM or less, 500 nM or less, 550 nMor less, 600 nM or less, 650 nM or less, 700 nM or less, 750 nM or less,800 nM or less, 850 nM or less, 900 nM or less, 950 nM or less, 1 μM orless, 1.1 μM or less, 1.2 μM or less, 1.3 μM or less, 1.4 μM or less,1.5 μM or less, 1.6 μM or less, 1.7 μM or less, 1.8 μM or less, 1.9 μMor less, 2 μM or less, 5 μM or less, 10 μM or less, 15 μM or less, 20 μMor less, 25 μM or less, 30 μM or less, 40 M or less, 50 μM, 60 μM, 70μM, 80 μM, 90 μM, 100 μM, 200 μM, 300 μM, 400 μM, or 500 μM, or less,(or a number in the range defined by and including any two numbersabove).

In some embodiments, the CDK inhibitor selectively inhibits CDK a withan IC50 value that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25,30, 35, 40, 45, 50, 100, or 1000 times less (or a number in the rangedefined by and including any two numbers above) than its IC50 valueagainst one, two, or three other CDKs.

In some embodiments, the CDK inhibitor selectively inhibits CDK a withan IC50 value that is less than about 1 nM, 2 nM, 5 nM, 7 nM, 10 nM, 20nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 120 nM, 140nM, 150 nM, 160 nM, 170 nM, 180 nM, 190 nM, 200 nM, 225 nM, 250 nM, 275nM, 300 nM, 325 nM, 350 nM, 375 nM, 400 nM, 425 nM, 450 nM, 475 nM, 500nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, 950nM, 1 M, 1.1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8 μM,1.9 μM, 2 μM, 5 μM, 10 M, 15 μM, 20 μM, 25 μM, 30 μM, 40 μM, 50 μM, 60μM, 70 μM, 80 μM, 90 μM, 100 μM, 200 M, 300 μM, 400 μM, or 500 μM (or inthe range defined by and including any two numbers above), and said IC50value is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40,45, 50, 100, or 1000 times less (or a number in the range defined by andincluding any two numbers above) than its IC50 value against one, two orthree other CDKs.

The subject methods are useful for treating a disease conditionassociated with CDK. Any disease condition that results directly orindirectly from an abnormal activity or expression level of CDK can bean intended disease condition.

Different disease conditions associated with CDK have been reported. CDKhas been implicated, for example, auto-immune diseases,neurodegeneration (such as Parkinson's disease, Alzheimer's disease andischaemia), inflammatory diseases, viral infections and cancer such as,for example, colon cancer, breast cancer, small-cell lung cancer,non-small-cell lung cancer, bladder cancer, ovarian cancer, prostatecancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloidleukemia, or pancreatic cancer.

Non-limiting examples of such conditions include but are not limited toAcanthoma, Acinic cell carcinoma, Acoustic neuroma, Acral lentiginousmelanoma, Acrospiroma, Acute eosinophilic leukemia, Acute lymphoblasticleukemia, Acute lymphocytic leukemia, Acute megakaryoblastic leukemia,Acute monocytic leukemia, Acute myeloblasts leukemia with maturation,Acute myeloid dendritic cell leukemia, Acute myeloid leukemia, Acutemyelogenous leukemia, Acute promyelocytic leukemia, Adamantinoma,Adenocarcinoma, Adenoid cystic carcinoma, Adenoma, Adenomatoidodontogenic tumor, Adrenocortical carcinoma, Adult T-cell leukemia,Aggressive NK-cell leukemia, AIDS-Related Cancers, AIDS-relatedlymphoma, Alveolar soft part sarcoma, Ameloblastic fibroma, Anal cancer,Anaplastic large cell lymphoma, Anaplastic thyroid cancer,Angioimmunoblastic T-cell lymphoma, Angiomyolipoma, Angiosarcoma,Appendix cancer, Astrocytoma, Atypical teratoid rhabdoid tumor, Basalcell carcinoma, Basal-like carcinoma, B-cell leukemia, B-cell lymphoma,Bellini duct carcinoma, Biliary tract cancer, Bladder cancer, Blastoma,Bone Cancer, Bone tumor, Brain Stem Glioma, Brain Tumor, Breast Cancer,Brenner tumor, Bronchial Tumor, Bronchioloalveolar carcinoma, Browntumor, Burkitt's lymphoma, Cancer of Unknown Primary Site, CarcinoidTumor, Carcinoma, Carcinoma in situ, Carcinoma of the penis, Carcinomaof Unknown Primary Site, Carcinosarcoma, Castleman's Disease, CentralNervous System Embryonal Tumor, Cerebellar Astrocytoma, CerebralAstrocytoma, Cervical Cancer, Cholangiocarcinoma, Chondroma,Chondrosarcoma, Chordoma, Choriocarcinoma, Choroid plexus papilloma,Chronic Lymphocytic Leukemia, Chronic monocytic leukemia, Chronicmyelogenous leukemia, Chronic Myeloproliferative Disorder, Chronicneutrophilic leukemia, Clear-cell tumor, Colon Cancer, Colorectalcancer, Craniopharyngioma, Cutaneous T-cell lymphoma, Degos disease,Dermatofibrosarcoma protuberans, Dermoid cyst, Desmoplastic small roundcell tumor, Diffuse large B cell lymphoma, Dysembryoplasticneuroepithelial tumor, Embryonal carcinoma, Endodermal sinus tumor,Endometrial cancer, Endometrial Uterine Cancer, Endometrioid tumor,Enteropathy-associated T-cell lymphoma, Ependymoblastoma, Ependymoma,Epidermoid cancer, Epithelioid sarcoma, Erythroleukemia, Esophagealcancer, Esthesioneuroblastoma, Ewing Family of Tumor, Ewing FamilySarcoma, Ewing's sarcoma, Extracranial Germ Cell Tumor, ExtragonadalGerm Cell Tumor, Extrahepatic Bile Duct Cancer, Extramammary Paget'sdisease, Fallopian tube cancer, Fetus in fetu, Fibroma, Fibrosarcoma,Follicular lymphoma, Follicular thyroid cancer, Gallbladder Cancer,Gallbladder cancer, Ganglioglioma, Ganglioneuroma, Gastric Cancer,Gastric lymphoma, Gastrointestinal cancer, Gastrointestinal CarcinoidTumor, Gastrointestinal Stromal Tumor, Gastrointestinal stromal tumor,Germ cell tumor, Germinoma, Gestational choriocarcinoma, GestationalTrophoblastic Tumor, Giant cell tumor of bone, Glioblastoma multiforme,Glioma, Gliomatosis cerebri, Glomus tumor, Glucagonoma, Gonadoblastoma,Granulosa cell tumor, Hairy Cell Leukemia, Head and Neck Cancer, Headand neck cancer, Heart cancer, Hemoglobinopathies such as b-thalassemiaand sickle cell disease (SCD), Hemangioblastoma, Hemangiopericytoma,Hemangiosarcoma, Hematological malignancy, Hepatocellular carcinoma,Hepatosplenic T-cell lymphoma, Hereditary breast-ovarian cancersyndrome, Hodgkin Lymphoma, Hodgkin's lymphoma, Hypopharyngeal Cancer,Hypothalamic Glioma, Inflammatory breast cancer, Intraocular Melanoma,Islet cell carcinoma, Islet Cell Tumor, Juvenile myelomonocyticleukemia, Kaposi Sarcoma, Kaposi's sarcoma, Kidney Cancer, Klatskintumor, Krukenberg tumor, Laryngeal Cancer, Laryngeal cancer, Lentigomaligna melanoma, Leukemia, Lip and Oral Cavity Cancer, Liposarcoma,Lung cancer, Luteoma, Lymphangioma, Lymphangiosarcoma,Lymphoepithelioma, Lymphoid leukemia, Lymphoma, Macroglobulinemia,Malignant Fibrous Histiocytoma, Malignant fibrous histiocytoma,Malignant Fibrous Histiocytoma of Bone, Malignant Glioma, MalignantMesothelioma, Malignant peripheral nerve sheath tumor, Malignantrhabdoid tumor, Malignant triton tumor, MALT lymphoma, Mantle celllymphoma, Mast cell leukemia, Mastocytosis, Mediastinal germ cell tumor,Mediastinal tumor, Medullary thyroid cancer, Medulloblastoma,Medulloblastoma, Medulloepithelioma, Melanoma, Melanoma, Meningioma,Merkel Cell Carcinoma, Mesothelioma, Mesothelioma, Metastatic SquamousNeck Cancer with Occult Primary, Metastatic urothelial carcinoma, MixedMullerian tumor, Monocytic leukemia, Mouth Cancer, Mucinous tumor,Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Multiplemyeloma, Mycosis Fungoides, Mycosis fungoides, Myelodysplasia Disease,Myelodysplasia Syndromes, Myeloid leukemia, Myeloid sarcoma,Myeloproliferative Disease, Myxoma, Nasal Cavity Cancer, NasopharyngealCancer, Nasopharyngeal carcinoma, Neoplasm, Neurinoma, Neuroblastoma,Neuroblastoma, Neurofibroma, Neuroma, Nodular melanoma, Non-HodgkinLymphoma, Non-Hodgkin lymphoma, Nonmelanoma Skin Cancer, Non-Small CellLung Cancer, Ocular oncology, Oligoastrocytoma, Oligodendroglioma,Oncocytoma, Optic nerve sheath meningioma, Oral Cancer, Oral cancer,Oropharyngeal Cancer, Osteosarcoma, Osteosarcoma, Ovarian Cancer,Ovarian cancer, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor,Ovarian Low Malignant Potential Tumor, Paget's disease of the breast,Pancoast tumor, Pancreatic Cancer, Pancreatic cancer, Papillary thyroidcancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer,Parathyroid Cancer, Penile Cancer, Perivascular epithelioid cell tumor,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumor ofIntermediate Differentiation, Pineoblastoma, Pituicytoma, Pituitaryadenoma, Pituitary tumor, Plasma Cell Neoplasm, Pleuropulmonaryblastoma, Polyembryoma, Precursor T-lymphoblastic lymphoma, Primarycentral nervous system lymphoma, Primary effusion lymphoma, PrimaryHepatocellular Cancer, Primary Liver Cancer, Primary peritoneal cancer,Primitive neuroectodermal tumor, Prostate cancer, Pseudomyxomaperitonei, Rectal Cancer, Renal cell carcinoma, Respiratory TractCarcinoma Involving the NUT Gene onChromosome 15, Retinoblastoma,Rhabdomyoma, Rhabdomyosarcoma, Richter's transformation, Sacrococcygealteratoma, Salivary Gland Cancer, Sarcoma, Schwannomatosis, Sebaceousgland carcinoma, Secondary neoplasm, Seminoma, Serous tumor,Sertoli-Leydig cell tumor, Sex cord-stromal tumor, Sezary Syndrome,Signet ring cell carcinoma, Skin Cancer, Small blue round cell tumor,Small cell carcinoma, Small Cell Lung Cancer, Small cell lymphoma, Smallintestine cancer, Soft tissue sarcoma, Somatostatinoma, Soot wart,Spinal Cord Tumor, Spinal tumor, Splenic marginal zone lymphoma,Squamous cell carcinoma, Stomach cancer, Superficial spreading melanoma,Supratentorial Primitive Neuroectodermal Tumor, Surfaceepithelial-stromal tumor, Synovial sarcoma, T-cell acute lymphoblasticleukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia,T-cell lymphoma, T-cell prolymphocytic leukemia, Teratoma, Terminallymphatic cancer, Testicular cancer, Thecoma, Throat Cancer, ThymicCarcinoma, Thymoma, Thyroid cancer, Transitional Cell Cancer of RenalPelvis and Ureter, Transitional cell carcinoma, Urachal cancer, Urethralcancer, Urogenital neoplasm, Uterine sarcoma, Uveal melanoma, VaginalCancer, Verner Morrison syndrome, Verrucous carcinoma, Visual PathwayGlioma, Vulvar Cancer, Waldenstrom's macroglobulinemia, Warthin's tumor,Wilms' tumor, or any combination thereof.

In some embodiments, said method is for treating a disease selected fromthe group consisting of tumor angiogenesis, chronic inflammatory diseasesuch as rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes, diabetic retinopathy, retinopathy of prematurity, age-relatedmacular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

In other embodiments, said method is for treating a disease selectedfrom breast cancer, lung cancer, pancreatic cancer, prostate cancer,colon cancer, ovarian cancer, uterine cancer, or cervical cancer.

In other embodiments, said method is for treating a disease selectedfrom leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),myelodysplastic syndrome (MDS) or epidermoid cancer.

Compounds of the disclosure, as well as pharmaceutical compositionscomprising them, can be administered to treat any of the describeddiseases, alone or in combination with a medical therapy. Medicaltherapies include, for example, surgery and radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, systemic radioactive isotopes).

In other aspects, compounds of the disclosure, as well as pharmaceuticalcompositions comprising them, can be administered to treat any of thedescribed diseases, alone or in combination with one or more otheragents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with agonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with antagonists of nuclear receptors agents.

In other methods, the compounds of the disclosure, as well aspharmaceutical compositions comprising them, can be administered incombination with an anti-proliferative agent.

In some embodiments, the disclosure is directed to methods for treatinga CDK4-mediated and a CDK6-mediated disorder in a patient in needthereof, comprising administering to said patient a compound of FormulaI, including all subgenera described herein, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising thecompound of Formula I, including all subgenera described herein.

In some embodiments, the CDK4-mediated and CDK6-mediated disorder is acancer. In some embodiments, the cancer is breast cancer, malignantbrain tumors, colon cancer, small-cell lung cancer, non-small-cell lungcancer, bladder cancer, ovarian cancer, prostate cancer, chroniclymphoid leukemia, lymphoma, myeloma, acute myeloid leukemia, secondarypancreatic cancer or secondary brain metastases.

In some embodiments, the cancer is breast cancer. In some embodiments,the cancer is malignant brain tumors. In some embodiments, the cancer iscolon cancer. In some embodiments, the cancer is small-cell lung cancer.In some embodiments, the cancer is non-small-cell lung cancer. In someembodiments, the cancer is bladder cancer. In some embodiments, thecancer is ovarian cancer.

In some embodiments, the cancer is prostate cancer. In some embodiments,the cancer is chronic lymphoid leukemia. In some embodiments, the canceris lymphoma. In some embodiments, the cancer is myeloma. In someembodiments, the cancer is acute myeloid leukemia. In some embodiments,the cancer is secondary pancreatic cancer. In some embodiments, thecancer is secondary brain metastases.

In some embodiments, the breast cancer is HR+/HER2− or HR+/HER2+advanced or metastatic breast cancer. In some embodiments, the breastcancer is HR+/IER2− advanced breast cancer. In some embodiments, thebreast cancer is HR+/IER2− metastatic breast cancer. In someembodiments, the breast cancer is HR+/HER2+ advanced breast cancer. Insome embodiments, the breast cancer is HR+/IER2+ metastatic breastcancer.

In some embodiments, the malignant brain tumors are glioblastoma,astrocytoma, or pontine glioma. In some embodiments, the malignant braintumors are a glioblastoma. In some embodiments, the malignant braintumors are an astrocytoma. In some embodiments, the malignant braintumors are a pontine glioma.

In some embodiments, the patient is administered a pharmaceuticalcomposition comprising a compound of Formula I, including all subgeneradescribed herein, or a pharmaceutically acceptable salt thereof. In someembodiments, the administration is oral administration.

Combination Therapies

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. The compounds of the invention can also beused in combination with a medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenictrioxide, asparaginase, azacitidine, bendamustine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase,pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin,procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine,vorinstat and zoledronate.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferase inhibitors, histonearginine methyl transferase inhibitors, histone demethylase inhibitors,histone deacetylase inhibitors, histone acetylase inhibitors, and DNAmethyltransferase inhibitors. Histone deacetylase inhibitors include,e.g., vorinostat. Histone arginine methyl transferase inhibitors includeinhibitors of protein arginine methyltransferases (PRMTs) such as PRMT5,PRMT1 and PRMT4. DNA methyltransferase inhibitors include inhibitors ofDNMT1 and DNMT3.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with targeted therapies,including JAK kinase inhibitors (e.g. Ruxolitinib), PI3 kinaseinhibitors including PI3K-delta selective and broad spectrum PI3Kinhibitors, MEK inhibitors, Cyclin Dependent kinase inhibitors,including CDK4/6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTORinhibitors, proteasome inhibitors (e.g. Bortezomib, Carfilzomib), HDACinhibitors (e.g. panobinostat, vorinostat), DNA methyl transferaseinhibitors, dexamethasone, bromo and extra terminal family member (BET)inhibitors, BTK inhibitors (e.g. ibrutinib, acalabrutinib), BCL2inhibitors (e.g. venetoclax), dual BCL2 family inhibitors (e.g.BCL2/BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), or PDR001. In some embodiments,the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In someembodiments, the anti-PD1 antibody is pembrolizumab. In someembodiments, the inhibitor of an immune checkpoint molecule is aninhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is atezolizumab,durvalumab, or BMS-935559. In some embodiments, the inhibitor of animmune checkpoint molecule is an inhibitor of CTLA-4, e.g., ananti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody isipilimumab.

In some embodiments, the agent is an alkylating agent, a proteasomeinhibitor, a corticosteroid, or an immunomodulatory agent. Examples ofan alkylating agent include cyclophosphamide (CY), melphalan (MEL), andbendamustine. In some embodiments, the proteasome inhibitor iscarfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

In some embodiments, the disclosure is directed to methods describedherein, further comprising administering an additional therapeutic agentto the patient. In some embodiments, the additional therapeutic agent isa PRMT5 inhibitor, a HER2 kinase inhibitor, an aromatase inhibitor, anestrogen receptor antagonist or an alkylating agent.

In some embodiments, the additional therapeutic agent is a PRMT5inhibitor. In some embodiments, the additional therapeutic agent is aHER2 kinase inhibitor. In other embodiments, the additional therapeuticagent is an aromatase inhibitor. In other embodiments, the additionaltherapeutic agent is an estrogen receptor antagonist. In yet otherembodiments, the additional therapeutic agent is an alkylating agent.

In some embodiments, the aromatase inhibitor is letrozole. In someembodiments, the estrogen receptor antagonist is fulvestrant. In otherembodiments, the alkylating agent is temozolomide.

In yet other embodiments, the PRMT5 inhibitor is a compound disclosed inUS Published Patent Application No. 2020/0148692 (filed Jan. 16, 2020);US Published Patent Application No. 2019/0284193 (filed Apr. 5, 2019);and US Published Patent Application No. 2019/0048014 (filed Aug. 9,2018); each of which is hereby incorporated herein in its entirety.

In some embodiments, the PRMT5 inhibitor is:

-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof;-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-7-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof;-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-difluoroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-5,6-difluoroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloro-5-fluoroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2R,3R,4S,5S)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6-chloroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2R,3R,4S,5S)-2-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-((R)-6,7-dichloroisochroman-1-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof;-   (2S,3S,4R,5R)-2-((R)-6,7-difluoroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2S,3S,4R,5R)-2-((R)-5,6-difluoroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2S,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof,-   (2S,3S,4R,5R)-2-((R)-6,7-dichloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol,    or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the PRMT5 inhibitor is(25,3S,4R,5R)-2-((R)-6-chloroisochroman-1-yl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol,or a pharmaceutically acceptable salt or solvate thereof.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of the invention can be prepared using numerous preparatoryreactions known in the literature. The Schemes below provide generalguidance in connection with preparing the compounds of the invention.One skilled in the art would understand that the preparations shown inthe Schemes can be modified or optimized using general knowledge oforganic chemistry to prepare various compounds of the invention. Examplesynthetic methods for preparing compounds of the invention are providedin the Schemes below.

The following Examples are provided to illustrate some of the conceptsdescribed within this disclosure. While the Examples are considered toprovide an embodiment, it should not be considered to limit the moregeneral embodiments described herein.

EXAMPLES General Synthetic Procedures

Compounds of Formula (I) can be prepared from optionally protected 1-1where W¹ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf orOMs) as shown in Scheme I. Compounds 1-1 can be coupled with compounds1-2 where M¹ is a boronic acid, boronate ester, potassiumtrifluoroborate, or an appropriately substituted metal, such as Sn(Bu)₃or ZnCl under standard Suzuki conditions (e.g., in the presence of apalladium catalyst, such as[1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base,such as K₃PO₄) or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such astetrakis(triphenyl-phosphine)palladium(0)) or standard Negishiconditions (e.g., in the presence of a palladium catalyst, such astetrakis(tri-phenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)), to givecompounds 1-3 where W² is halogen (e.g., Cl, Br, or I) or pseudohalogen(e.g., OTf or OMs). Coupling of compounds 1-3 with amines 1-4 understandard Buchwald-Hartwig amination conditions (e.g., in the presence ofa palladium catalyst, such as XPhos Pd G2, and a base, such as K₃PO₄)can provide compounds of Formula (I).

Alternatively, compounds 1-1 can be converted to the appropriatecompounds 1-5 (e.g., M² is B(OH)₂, Bpin, BF₃K, Sn(Me)₃, Sn(Bu)₃, orZnCl) and then coupled to 1-6 where W³ is halogen (e.g., Cl, Br, or I)or pseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions(e.g., in the presence of a palladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), and abase, such as K₃PO₄) or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine) palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to givecompounds 1-3, which can be used to synthesize compound of Formula (I).

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme II. Compounds 2-1 can be halogenatedwith suitable reagents, such as N-bromo-succinimide orN-iodosuccinimide, to provide compounds 1-1. Alternatively, compounds2-1 can be metalated in the presence of a strong base, such as lithiumdiisopropylamide or butyllithium, and an appropriate reagent (e.g.,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, hexamethylditin,trimethyltin chloride, or zinc chloride) to afford compounds 1-5.

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme III. Coupling of compounds 3-1 where W⁴is halogen (e.g., C₁, Br, or I) or pseudohalogen (e.g., OTf or OMs) withamines 3-2 under either standard Buchwald-Hartwig amination conditions(e.g., in the presence of a palladium catalyst, such as XPhos Pd G2, anda base, such as K₃PO₄) or standard conditions for nucleophilic aromaticsubstitution optionally in the presence of a base (e.g.,diisopropylethylamine) can provide compounds 3-3. Nitro compounds 3-3can be reduced to amino compounds 3-4 under standard reductiveconditions such as, but not limited to, H₂ in the presence of atransition metal catalyst (e.g., palladium on charcoal) in MeOH,Fe/NH₄Cl in MeOH/H₂O, or sodium dithionite in EtOH/H₂O. Compounds 3-4can be employed in Scheme I to afford compounds of Formula (I).

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme IV from compounds 4-1 where M³ is aboronic acid, boronate ester, potassium trifluoroborate, or anappropriately substituted metal, such as Sn(Bu)₃ or ZnCl; R^(x), R^(y),and R^(z) are independently H, D, C₁-C₅ alkyl, 5-7 membered aryl, 5-7membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or 7-memberedheterocycloalkyl wherein said C₁-C₅ alkyl groups, 5-7 membered aryl, 5-7membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or 7-memberedheterocycloalkyl may be optionally substituted; and optionally R^(X) andR^(z), together with alkene to which they are both attached, may form acycloalkenyl or heterocycloalkenyl group. Compounds 4-1 can be coupledwith compounds 4-2 where Y¹ is halogen (e.g., C₁, Br, or I) orpseudohalogen (e.g., OTf or OMs) under standard Suzuki conditions (e.g.,in the presence of a palladium catalyst, such as[1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and a base,such as K₃PO₄) or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0))or standard Negishi conditions (e.g., in the presence of a palladiumcatalyst, such as tetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II)), to givecompounds 4-3. Alkenes 4-3 can be converted to compounds 4-4 underreductive conditions such as, but not limited to, H₂ in the presence ofa transition metal catalyst (e.g., palladium on charcoal) in alcoholsolvent (e.g., MeOH or EtOH).

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme V from compounds 5-1 where R^(v) andR^(w) are independently H, D, C₁-C₅ alkyl, 5-7 membered aryl, 5-7membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or 7-memberedheterocycloalkyl wherein said C₁-C₅ alkyl, 5-7 membered aryl, 5-7membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or 7-memberedheterocycloalkyl may be optionally substituted, and optionally R^(v) andR^(w), together with carbon to which they are both attached, may form acyclic ketone. Reaction with amines 5-2 where R^(q) is a C₁-C₆ alkylgroup under standard conditions for reductive amination (e.g., in thepresence of a reducing agent such as sodium triacetoxyborohydride andoptionally an acid, such as acetic acid) can provide compounds 5-3.Hydrolysis of esters 5-3 under standard conditions (e.g., in thepresence of a base, such as NaOH, or an acid, such as HCl) can providecarboxylic acids 5-4. Amines 5-4 can be coupled to compounds 5-5 whereY¹ is Cl when compound 5-5 is an acid chloride or —OC(═O)R^(s) whereR^(s) is a C₁-C₆ alkyl when compound 5-5 is an acid anhydride underappropriate conditions (e.g., in the presence of a base such astriethylamine and optionally a catalyst such as4-(dimethylamino)pyridine) to afford amides 5-6. Curtius rearrangementof compounds 5-6 under standard conditions, such as in the presence ofdiphenyl phosphoryl azide, and base, such as triethylamine, andsubsequent exposure to aqueous conditions (e.g., dioxane/water) canafford compounds 5-7. Cyclization of 5-7 under appropriate conditionssuch as in the presence of a dehydrating agent (e.g., phosphorousoxychloride) can provide compounds 5-8.

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme VI. Carboxylic acids 6-1 can beconverted the appropriate acid chlorides 6-2 under standard conditions(e.g., in the presence of a reagent such as oxalyl chloride or thionylchloride and optionally a catalyst such as N,N-dimethylformamide).Reaction with hydroxyl amine or its salts (e.g., NH₂OH.HCl) underappropriate conditions (e.g., in the presence of a base, such as sodiumhydroxide) can afford hydroxamic acids 6-3. Compound 6-3 can be acylatedwith acid chlorides 6-4 where RP is a C₁-C₆ alkyl group underappropriate conditions (e.g., in the presence of a base, such astriethylamine) to afford compounds 6-5. Compounds 6-5 can be coupledwith compounds 6-6 where R⁹ and R^(h) are each independently R³ understandard transition-metal-catalyzed C—H activation conditions (e.g., inthe presence of a rhodium catalyst, such aspentamethylcyclopentadienyl-rhodium(III) chloride dimer, and a base,such as cesium acetate) to afford compounds 6-8. Alternatively,compounds 6-5 can be coupled with compounds 6-6 where R^(g) and R^(h)are each independently R³ under standard transition-metal-catalyzed C—Hactivation conditions (e.g., in the presence of a rhodium catalyst, suchas pentamethylcyclopentadienyl-rhodium(III) chloride dimer, and a base,such as cesium acetate) to afford compounds 6-8 where R^(g) and R^(h)are each H. Dehydrative halogenation of compounds 6-8 (e.g., by treatingwith a reagent such as POCl₃ or POBr₃) can afford compounds 6-9 where Y²is halogen (e.g., Cl or Br).

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme VII. Carbonyl compound 7-1 where R¹ isC₁-C₅ alkyl, 5-7 membered aryl, 5-7 membered heteroaryl, cycloalkyl, or4-, 5-, 6- or 7-membered heterocycloalkyl wherein said C₁-C₅ alkylgroups, 5-7 membered aryl, 5-7 membered heteroaryl, cycloalkyl, or 4-,5-, 6- or 7-membered heterocycloalkyl may be optionally substituted canbe reacted with an organometallic reagent 7-2 where M⁴ is an appropriatemetal (e.g., Li, MgCl, MgBr, ZnCl, or ZnR^(j)) and R^(j) is C₁-C₅ alkyl,5-7 membered aryl, 5-7 membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or7-membered heterocycloalkyl wherein said C₁-C₅ alkyl groups, 5-7membered aryl, 5-7 membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or7-membered heterocycloalkyl may be optionally substituted to affordalcohols 7-3. Alternatively, compounds 7-1 can be converted to alcohols7-5 where Z¹ is a fluoroalkyl group (e.g., CF₃ or CF₂H) upon reactionwith silane 7-4 where Y³ is a halogen (e.g., F or Br) or H understandard conditions (e.g., in the presence of tetrabutylammoniumfluoride or triphenyl phosphine and N,N′-dimethylpropylene urea).

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme VIII. Oxidation of compounds 8-1 understandard conditions, such as in the presence of a peroxyacid (e.g.,mCPBA) or a peroxide (e.g., urea-hydrogen peroxide adduct), can affordN-oxides 8-2.

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme IX. Reaction of thiophenes 9-1 withcompounds 9-2 where Y⁴ is a halogen (e.g., Cl or Br) under standardconditions, such as in the presence of a Lewis acid (e.g., aluminumchloride), can afford compounds 9-3. Ketones 9-3 can be reacted withcompound 9-4 where R^(o) and R^(r) are each independently C₁-C₆ alkylunder standard conditions in the presence of a base (e.g., sodiumhydride, butyllithium, or isopropylmagnesium chloride) to affordα,β-unsaturated esters 9-5. Hydrolysis of esters 9-5 under standardconditions (e.g., in the presence of a base, such as NaOH, or an acid,such as HCl) can provide carboxylic acids 9-6. Curtius rearrangement ofcompounds 9-6 under standard conditions, such as in the presence ofdiphenyl phosphoryl azide, and base, such as triethylamine, andsubsequent cyclization under standard conditions can afford compounds9-7. Alkylation of compounds 9-7 with halides 9-8 where Y⁵ is a halide(e.g., Cl, Br, or I) and R^(n) is a —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, C₁alk-aryl, C₁alk-heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group can provide compounds 9-9.

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme X. Coupling of compounds 3-1 withcompounds 10-1 where x and y are independently 0, 1, 2, or 3; where Q¹is H or a protecting group, such as Boc, Cbz, Bn, PMB, Trt, acetamido,or trifluoracetamido; and where M⁵ is a boronic acid, boronate ester,potassium trifluoroborate, or an appropriately substituted metal, suchas Sn(Bu)₃ or ZnCl, under standard Suzuki conditions (e.g., in thepresence of a palladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a base,such as K₃PO₄ or K₂CO₃) or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) or standard Negishi conditions(e.g., in the presence of a palladium catalyst, such astetrakis(triphenylphosphine) palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)), and thenoptional deprotection can provide compounds 10-2. Alkylation of amines10-2 with halides 10-3 where Y⁶ is a halide (e.g., Cl, Br, or I) orpseudohalide (e.g., OTf, OTs, or OMs) and R^(a) is a —C₁-C₆alkyl,—C₂-C₆alkenyl, —C₂-C₆alkynyl, C₁alk-aryl, C₁alk-heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group can providecompounds 10-4. Compounds 10-4 can be reduced to amines 10-5 understandard reductive conditions such as, but not limited to, H₂ in thepresence of a transition metal catalyst (e.g., palladium on charcoal orplatinum(IV) oxide).

Alternatively, reaction of amines 10-2 under standard conditions forreductive amination (e.g., in the presence of a reducing agent such assodium triacetoxyborohydride or sodium cyanoborohydride and optionallyan acid, such as acetic acid) with compounds 10-6 where R^(b) and R^(c)are each independently H, D, C₁-C₆ alkyl, 5-7 membered aryl, 5-7membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or 7-memberedheterocycloalkyl wherein said C₁-C₅ alkyl, 5-7 membered aryl, 5-7membered heteroaryl, cycloalkyl, or 4-, 5-, 6- or 7-memberedheterocycloalkyl may be optionally substituted and optionally R^(b) andR^(c), together with carbon to which they are both attached, may form acyclic ketone can provide compounds 10-7. Compounds 10-7 can be reducedto amines 10-8 under standard reductive conditions such as, but notlimited to, H₂ in the presence of a transition metal catalyst (e.g.,palladium on charcoal or platinum(IV) oxide).

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme XI. Metalation of halides 11-1 where W³is a halogen (e.g., Br or I) under standard metal-halogen exchangeconditions (e.g., in the presence of magnesium metal, Grignard reagents(e.g., isopropylmagnesium bromide) or alkyllithium reagents, such asbutyllithium) and subsequent addition to pyrimidines 11-2 where W² ishalogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) canprovide compounds 11-3. Compounds 11-3 can be oxidized to heteroaromaticcompounds 1-3 under standard oxidative conditions such as, but notlimited to, in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone.

Compounds of Formula (I) can be prepared from compounds 1-3 as shown inScheme XII. Compounds 1-3 can reacted under standard nucleophilicaromatic substitution conditions (e.g., in the presence of anhydrous NH₃or NH₄OH (aq.)) or standard Buchwald-Hartwig amination conditions (e.g.,in the presence of an ammonia surrogate such as benzophenone imine,lithium bis(trimethylsilyl)amide, or tert-butyl carbamate; a palladiumcatalyst, such as Pd₂(dba)₃; a ligand, such as XPhos or XantPhos; andoptionally base, such as Cs₂CO₃) or standard Ullman coupling conditions(e.g., in the presence of an ammonia source, such as NH₃ or ammoniumbicarbonate, and a copper catalyst, such as CuO, CuSO₄, or CuI) toprovide amino pyrimidines 12-1. Coupling of compounds 12-1 with halides12-2 where W⁵ is halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g.,OTf or OMs) under standard Buchwald-Hartwig amination conditions (e.g.,in the presence of a palladium catalyst, such as XPhos Pd G2 orBrettPhos Pd G3, and a base, such as sodium tert-butoxide or K₃PO₄) canprovide compounds of Formula (I).

Intermediates for the synthesis of compounds Formula (I) can be preparedas described in Scheme XIII. Reduction of esters 13-1 where R^(s) is a—C₁-C₆ alkyl group under standard conditions (e.g., in the presence oflithium aluminum hydride) can provide compounds 13-2. Acylation ofcompounds 13-2 with anhydrides 13-3 where R^(t) is a C₁-C₆ alkyl groupunder standard conditions (e.g., in the presence of potassium acetate)and subsequent nitrosation/cyclization under standard conditions, suchas in the presence of an alkyl nitrite (e.g., isoamyl nitrite), canafford compounds 13-4. Hydrolysis of acyl thienopyrazoles 13-4 understandard conditions (e.g., in the presence of a base, such as NaOH, oran acid, such as HCl) can provide thienopyrazoles 13-5. Compounds 13-5can be halogenated with suitable reagents, such as iodine, bromine, orN-bromosuccinimide, optionally in the presence of a base (e.g.,potassium carbonate or sodium hydroxide) to afford the compounds 13-6where W⁶ is a halogen (e.g., Br or I). Alkylation of thienopyrazoles13-6 with electrophiles 13-7 where Y⁸ is a halogen (e.g., Cl, Br, or I)or pseudohalogen (e.g., OTf, OTs, or OMs) or other leaving group (e.g.,dimethyloxonium) and R^(u) is a —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, C₁alk-aryl, C₁alk-heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group can provide compounds13-8. Heteroaryl halides 13-8 can be coupled with the appropriatecompounds 13-9 (e.g., M⁶ is B(OH)₂, Bpin, BF₃K, Sn(Me)₃, Sn(Bu)₃, orZnCl) under standard Suzuki conditions (e.g., in the presence of apalladium catalyst, such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base,such as K₃PO₄) or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0))or standard Negishi conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to givecompounds 13-10.

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme XIV. Friedel-Crafts acylation ofcompounds 2-1 with acid halides 14-1 where R^(k) is H, D, F, C₁-C₈alkoxide, C₁-C₈ alkyl, fluoroalkyl, or CN and Y⁹ is a halogen (e.g., Clor Br) under standard conditions, such as in the presence of a Lewisacid (e.g., AlCl₃), can afford ketones 14-2. Condensation of compounds14-2 with acetal 14-3 where R¹ is H, D, —C₁-C₈ alkoxide, —C₁-C₈ alkyl,fluoroalkyl, or CN can afford compounds 14-4. Subsequent condensation ofcompounds 14-4 with guanidine or one of its salts (e.g., guanidinehydrochloride) optionally in the presence of a base (e.g., K₂CO₃) canafford amino pyrimidines 14-5.

Intermediates for the synthesis of compounds of Formula (I) can beprepared as described in Scheme XV. Compounds 13-8 can be coupled withcompounds 4-1 under standard Suzuki conditions (e.g., in the presence ofa palladium catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base, such as K₃PO₄) or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0)) or standard Negishiconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis (triphenylphosphine)palladium(0) or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) to givecompounds 15-1. Alkenes 15-1 can be converted to compounds 15-2 underreductive conditions such as, but not limited to, H₂ in the presence ofa transition metal catalyst (e.g., palladium on charcoal) in alcoholsolvent (e.g., MeOH or EtOH).

Example 1.4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine

Step 1: Methyl 2-(cyclopentylamino)-4-methylthiophene-3-carboxylate

NaBH(OAc)₃ (18.382 g, 86.7 mmol, 2.50 equiv.) was added portionwise to asolution of methyl 2-amino-4-methylthiophene-3-carboxylate (5.940 g,34.7 mmol, 1.00 equiv.), cyclo-pentanone (7.556 g, 86.7 mmol, 2.50equiv.), and acetic acid (5.209 g, 86.7 mmol, 2.50 equiv.) in DCE (120mL). The resulting suspension was stirred at ambient temperature for 18h. The reaction mixture was slowly poured over 10% Na₂CO₃ solution (200mL) and stirred until gas evolution ceased. The organic layer wasseparated, and the aqueous layer extracted with DCM (50 mL×3). Thecombined organic phase was washed with H₂O (50 mL) and brine (50 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel (80 g)(0-5% MTBE in heptanes) to give the title compound (5.221 g, 21.8 mmol,62.9% yield) as colorless oil. R_(f)=0.6 (10% MTBE in heptanes). LCMScalc. for C₁₂H₁₈NO₂S [M+H]⁺: m/z=240.1; Found: 240.0.

Step 2. 2-(Cyclopentylamino)-4-methylthiophene-3-carboxylic Acid

Powder NaOH (8.276 g, 218.2 mmol, 10.0 equiv.) was dissolved in H₂O (30mL) and the resulting aqueous solution was slowly added to the solutionof methyl 2-(cyclopentylamino)-4-methylthiophene-3-carboxylate (5.221 g,21.8 mmol, 1.00 equiv.) in MeOH (30 mL) at ambient temperature. Thereaction mixture was heated at 80° C. for 18 h. The organic solvent wasevaporated under reduced pressure. The remaining aqueous solution wasdiluted with H₂O (30 mL), acidified with 4 N HCl solution (to pH 3-4),and extracted with MTBE (50 mL×3). The combined organic phase was washedwith H₂O (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, andevaporated in vacuo to give the title compound (4.175 g, 18.5 mmol,85.0% yield) as an amber solid. R_(f)=0.3 (30% MTBE in heptanes). LCMScalc. for C₁₁H₁₆NO₂S [M+H]⁺: m/z=226.1; Found: 226.0.

Step 3. 2-(N-Cyclopentylacetamido)-4-methylthiophene-3-carboxylic Acid

Acetic anhydride (4.729 g, 46.3 mmol, 2.50 equiv.) was added dropwiseinto the solution of 2-(cyclopentylamino)-4-methylthiophene-3-carboxylicacid (4.175 g, 18.5 mmol, 1.00 equiv.), Et3N (5.625, 55.6 mmol, 3.00equiv.), and DMAP (226 mg, 1.85 mmol, 0.10 equiv.) in DCM (50 mL). Theresulting mixture was stirred at room temperature for 18 h. The reactionmixture was poured over cold saturated NH4Cl solution (100 mL). Theorganic layer was separated and the aqueous layer extracted twice withDCM (50 mL). The combined organic phase was washed with H2O (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered, and evaporated in vacuo. Thecrude product was purified by flash chromatography on silica gel (0-50%EtOAc in heptanes as eluent) to give the title compound (3.897 g, 14.6mmol, 78.8% yield) as a yellow viscous oil. R_(f)=0.2 (50% EtOAc inheptanes). LCMS calc. for C₁₃H₁₈NO₃S [M+H]⁺: m/z=268.1; Found: 268.0.

Step 4. N-(3-Amino-4-methylthiophen-2-yl)-N-cyclopentylacetamide

To the solution of 2-[acetyl(cyclopentyl)amino]thiophene-3-carboxylicacid (3.897 g, 14.6 mmol) and Et₃N (7.375 g, 72.9 mmol, 5.00 equiv.) in1,4-dioxane (40 mL), DPPA (10.029 g, 36.4 mmol, 2.50 equiv.) was addeddropwise. The reaction mixture was stirred at room temperature for 1 h.H2O (40 mL) was added and the reaction was heated to reflux for 18 h.The reaction mixture was cooled to room temperature and 2 M NaOHsolution (20 mL) was added and the resulting mixture was further stirredat room temperature for 30 min. The reaction mixture was poured oversaturated NH₄Cl solution (30 mL) and extracted with DCM (50 mL×3). Thecombined organic phase was washed with H₂O (50 mL) and brine (50 mL),dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude product was used in the next step without furtherpurification.

Step 5. 3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole

To the solution ofN-(3-amino-4-methylthiophen-2-yl)-N-cyclopentylacetamide (crude, fromprevious step, 4.118 g, 17.3 mmol, 1.00 equiv.) in toluene (40 mL),POCl3 (2.782 g, 18.1 mmol, 1.05 mmol) was added dropwise at ambienttemperature. The resulting solution was heated at 100° C. for 18 h. Thereaction mixture was cooled to room temperature and poured over 10%Na2CO3 solution. The organic layer was separated, and the aqueous layerextracted with EtOAc (3 mL×3). The combined organic phase was washedwith brine (15 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel column (0%-75% EtOAc and 0.1% Et3N in heptanes) to give thetitle compound (1.547 g, 7.02 mmol, 40.6% yield) as amber oil. R_(f)=0.2(50% EtOAc in heptanes). LCMS calc. for C₁₂H₁₇N₂S [M+H]⁺: m/z=221.1;Found: 221.0.

Step 6.3-Cyclopentyl-2,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-thieno[2,3-d]imidazole

The solution of LDA (1.29 mL, 9.74 mmol, 5.00 equiv.) in THE and hexanes(1.40 M) was added dropwise to the solution of3-cyclopentyl-2,6-dimethylthieno[2,3-d]imidazole (429 mg, 1.95 mmol,1.00 equiv.) and4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane (725 mg, 3.89mmol, 2.00 equiv.) in THE (10 mL) at −78° C. The reaction mixture wasstirred at −78° C. and monitored with LCMS. When LCMS analysis indicatedthe complete consumption of the starting material (-1 h), the reactionwas quenched by the dropwise addition of saturated NH4Cl (15 mL). Theresulting mixture was extracted with CHCl₃/iPrOH (1:1, 20 mL x 3). Thecombined organic phase was washed with H₂O (10 mL) and brine (10 mL),dried over anhydrous Na₂SO₄, filtered, and evaporated in vacuo. Theresidue was used in the next step without further purification. LCMScalc. for C₁₈H₂₈BN₂O_(2S) [M+H]⁺: m/z=347.2; Found: 347.1.

Step 7.5-(2-Chloro-5-fluoropyrimidin-4-yl)-3-cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole

To the crude boronate ester in 1,4-dioxane (8 mL) was added2,6-dichloro-5-fluororacil (285 mg, 1.71 mmol, 1.00 equiv.), Pd(dppf)Cl₂(62 mg, 0.09 mmol, 0.05 equiv.), K₃PO₄ (1.449 g, 6.83 mmol, 4.00equiv.), and H₂O (2 mL). The resulting mixture was stirred at 100° C.under a nitrogen atmosphere for 6 h, when TLC analysis showed thedisappearance of the starting material. The reaction mixture was cooledto ambient temperature and partitioned between H₂O (15 mL) and EtOAc (15mL). The organic layer was separated and the aqueous phase was extractedwith EtOAc (15 mL×3). The combined organic phase was washed with brine(15 mL), dried over anhydrous Na2SO4, filtered, and evaporated in vacuo.The residue was purified by flash column chromatography (0-50% EtOAc inheptanes) to give the title compound (120 mg, 0.34 mmol, 20.0% yield) asyellow solid. R_(f)=0.25 (50% EtOAc in heptanes). LCMS calc. forC₁₆H₁₇ClFN₄S [M+H]⁺m/z=351.1; Found: 351.0.

Step 8.4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethyl-piperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine

The suspension of5-(2-chloro-5-fluoropyrimidin-4-yl)-3-cyclopentyl-2,6-dimethylthieno[2,3-d]imidazole(70.0 mg, 0.20 mmol, 1.00 equiv.),5-(4-ethylpiperazin-1-yl)pyridin-2-amine (41.0 mg, 0.20 mmol, 1.00equiv.), XPhos Pd G2 (7.9 mg, 0.01 mmol, 0.05 equiv.), and K₃PO₄ (169.0mg, 0.80 mmol, 4.00 equiv.) in 1,4-dioxane (2 mL) was heated at 100° C.under N₂ atmosphere for 18 h. The reaction mixture was cooled to roomtemperature and TFA (2 drops) was added. The inorganic salts werefiltered off and the filtrate was purified by Prep-HPLC on a C₁₈ column(6%-80% MeCN in H₂O) to give the title compound as its HCl salt (46.2mg, 0.09 mmol, 43.6% yield), light yellow solid. ¹H NMR (300 MHz, CD₃OD)δ 8.81 (d, J=3.0 Hz, 1H), 8.28 (dd, J=9.7, 2.8 Hz, 1H), 7.95 (d, J=2.7Hz, 1H), 7.59 (d, J=9.6 Hz, 1H), 5.15-5.02 (m, 1H), 3.97 (t, J=10.8 Hz,2H), 3.74 (t, J=10.6 Hz, 2H), 3.40-3.33 (m, 2H), 3.28-3.24 (m, 2H), 2.89(s, 3H), 2.74 (d, J=3.1 Hz, 3H), 2.46-2.33 (m, 2H), 2.27-1.78 (m, 7H),1.44 (t, J=7.3 Hz, 3H). LCMS calc. for C₂₇H₃₄FN₈S [M+H]⁺: m/z=521.3;Found: 520.9.

Examples listed in Tables 1-1 and 1-2 are synthesized according toprocedures analogous to Example 1.

TABLE 1-1 Examples 2-13 Exam- LCMS ple R₁ R₂ R₃ [M + H]⁺ 2 Me iso-propyl

495.1 3 Me iso- propyl

509.3 4 Me cyclo- butyl

507.2 5 Me cyclo- pentyl

520.1 6 Me cyclo- pentyl

506.1 7 Me cyclo- pentyl

507.2 8 Me cyclo- butyl

506.2 9 Me iso- propyl

481.1 10 Me cyclo- butyl

521.2 11 Me cyclo- pentyl

513.8 12 Me cyclo- pentyl

535.0 13 H cyclo- pentyl

493.1

TABLE 1-2 Examples 2-13 Example Compound name NMR 2N-(5-(4-Ethylpiperazin-1- ¹H NMR (300 MHz, CD₃OD) δ 8.78yl)pyridin-2-yl)-5-fluoro-4-(3- (d, J = 3.1 Hz, 1H), 8.25 (dd, J = 9.7,2.9 isopropyl-2,6-dimethyl-3H- Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.63thieno[2,3-d]imidazol-5- (d, J = 9.6 Hz, 1H), 5.01-4.92 (m, 1H),yl)pyrimidin-2-amine 3.97-3.91 (m, 2H), 3.77-3.71 (m, 2H), 3.43-3.13 (m,6H), 2.86 (s, 3H), 2.75 (d, J = 3.0 Hz, 3H), 1.68 (d, J = 6.7 Hz, 6H),1.44 (t, J = 7.3 Hz, 3H). 3 N-(5-((4-Ethylpiperazin-1- ¹H NMR (300 MHz,CD₃OD) δ 8.81 yl)methyl)pyridin-2-yl)-5-fluoro- (d, J = 3.0 Hz, 1H),8.37-8.31 (m, 2H), 7.70- 4-(3-isopropyl-2,6-dimethyl-3H- 7.63 (m, 1H),5.01-4.92 (m, 1H), 3.77 (s, thieno[2,3-d]imidazol-5- 2H), 3.32-3.04 (m,9H), 2.88 (d, J = 2.9 yl)pyrimidin-2-amine Hz, 3H), 2.75 (d, J = 3.0 Hz,3H), 2.04 (s, 2H), 1.68 (d, J = 6.7 Hz, 6H), 1.36 (t, J = 7.3 Hz, 3H). 44-(3-Cyclobutyl-2,6- ¹H NMR (300 MHz, CD₃OD) δ 8.76dimethylthieno[2,3-d]imidazol-5- (d, J = 3.1 Hz, 1H), 8.24 (dd, J = 9.7,2.9 Hz, yl)-N-[5-(4-ethylpiperazin-1- 1H), 7.93 (d, J = 2.7 Hz, 1H),7.62 (d, J = yl)pyridin-2-yl]-5-fluoro- 9.6 Hz, 1H), 5.25-5.02 (m, 1H),4.14- pyrimidin-2-amine 3.37 (m, 8H), 3.28-3.20 (m, 2H), 2.79 (s, 3H),2.74 (d, J = 3.0 Hz, 3H), 2.71-2.61 (m, 4H), 2.11-2.03 (m, 2H), 1.42 (t,J = 7.3 Hz, 3H). 5 4-(3-Cyclopentyl-2,6-dimethyl- ¹H NMR (300 MHz,CD₃OD) δ 8.55 3H-thieno[2,3-d]imidazol-5-yl)- (d, J = 3.1 Hz, 1H),8.16-8.02 (m, 2H), 7.46 N-(5-(1-ethylpiperidin-4- (d, J = 9.7 Hz, 1H),4.85-4.80 (m, 1H), yl)pyridin-2-yl)-5-fluoro- 3.58-3.49 (m, 1H), 3.02(q, J = 7.4 Hz, pyrimidin-2-amine 2H), 2.97-2.86 (m, 3H), 2.62 (d, J =6.6 Hz, 3H), 2.53 (d, J = 3.1 Hz, 3H), 2.45 (d, J = 3.3 Hz, 1H),2.21-2.01 (m, 4H), 1.91- 1.79 (m, 6H), 1.71-1.64 (m, 2H), 1.19 (t, J =7.3 Hz, 3H). 6 4-(3-Cyclopentyl-2,6-dimethyl- —3H-thieno[2,3-d]imidazol-5-yl)- 5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine 7 4-(3-Cyclopentyl-2,6-dimethyl- ¹HNMR (300 MHz, CD₃OD) δ 8.44 3H-thieno[2,3-d]imidazol-5-yl)- (d, J = 3.3Hz, 1H), 7.88 (dd, J = 9.6, 2.9 Hz, 5-fluoro-N-(5-(4-methyl- 1H), 7.71(s, 1H), 7.49 (d, J = 9.6 Hz, 1H), piperazin-1-yl)pyridin-2- 5.01-4.92(m, 1H), 3.39-3.17 (m, 4H), yl)pyrimidin-2-amine 2.99-2.84 (m, 4H), 2.79(s, 3H), 2.53 (s, 3H), 2.51 (d, J = 3.0 Hz, 3H), 2.20-2.03 (m, 2H),1.90-1.64 (m, 6H). 8 4-(3-Cyclobutyl-2,6-dimethyl- ¹H NMR (300 MHz,CD₃OD) δ 8.81 3H-thieno[2,3-d]imidazol-5-yl)- (d, J = 3.0 Hz, 1H),8.47-8.25 (m, 2H), 7.67 N-(5-(1-ethylpiperidin-4- (s, 1H), 5.20 (q, J =8.8 Hz, 1H), 3.75 (d, J = yl)pyridin-2-yl)-5-fluoro- 12.7 Hz, 2H),3.31-3.08 (m, 6H), 2.80 pyrimidin-2-amine (d, J = 1.9 Hz, 3H), 2.75 (t,J = 2.5 Hz, 4H), 2.71-2.61 (m, 3H), 2.25 (d, J = 14.3 Hz, 2H), 2.08 (td,J = 10.3, 4.1 Hz, 4H), 1.41 (t, J = 7.3 Hz, 3H). 95-Fluoro-4-(3-isopropyl-2,6- 1H NMR (300 MHz, CD₃OD) δ 8.78dimethyl-3H-thieno[2,3- (d, J = 3.1 Hz, 1H), 8.25 (dd, J = 9.7, 2.9d]imidazol-5-yl)-N-(5-(4- Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.63methylpiperazin-1-yl)pyridin-2- (d, J = 9.6 Hz, 1H), 5.01-4.92 (m, 1H),yl)pyrimidin-2-amine, HCl salt 3.99-3.82 (m, 2H), 3.75-3.60 (m, 2H),3.45-3.30 (m, 4H), 3.02 (s, 3H), 2.86 (s, 3H), 2.75 (d, J = 3.0 Hz, 3H),1.68 (d, J = 6.7 Hz, 6H). 10 4-(3-Cyclobutyl-2,6- ¹H NMR (300 MHz,CD₃OD) δ 8.88 dimethylthieno[2,3-d]imidazol-5- (d, J = 2.9 Hz, 1H), 8.56(s, 1H), 8.50 (d, J = yl)-N-[5-[(4-ethylpiperazin-1- 9.1 Hz, 1H), 7.68(d, J = 9.1 Hz, 1H), 5.25- yl)methyl]pyridin-2-yl]-5- 5.15 (m, 1H), 4.22(s, 2H), 4.14-3.37 fluoropyrimidin-2-amine, HCl (m, 8H), 3.23-3.09 (m,2H), 2.84 (d, J = salt 7.6 Hz, 3H), 2.77 (d, J = 3.0 Hz, 3H), 2.69 (m,4H), 2.14-2.05 (m, 2H), 1.41 (t, J = 7.3 Hz, 3H). 114-(3-Cyclopentyl-2,6-dimethyl- ^(1H) NMR (300 MHz, CD₃OD) δ 8.723H-thieno[2,3-d]imidazol-5-yl)- (d, J = 3.2 Hz, 1H), 7.86 (dd, J = 9.5,2.9 Hz, N-(5-(3,3-difluoropyrrolidin-1- 1H), 7.54 (t, J = 6.0 Hz, 2H),5.06 (dt, J = yl)pyridin-2-yl)-5-fluoro- 15.4, 7.7 Hz, 1H), 3.78-3.57(m, 4H), pyrimidin-2-amine 2.83 (s, 3H), 2.73 (d, J = 3.1 Hz, 3H), 2.67-2.55 (m, 2H), 2.43-2.31 (m, 2H), 2.17- 1.86 (m, 6H). 124-(3-Cyclopentyl-2,6-dimethyl- — 3H-thieno[2,3-d]imidazol-5-yl)-N-(5-((4-ethylpiperazin-1- yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine 13 4-(3-Cyclopentyl-2-methyl-3H- ¹H NMR (300MHz, CD₃OD) δ 8.78 thieno[2,3-d]imidazol-5-yl)-5- (d, J = 2.8 Hz, 1H),8.27 (d, J = 8.5 Hz, 1H), fluoro-N-(5-(4-methylpiperazin- 8.15 (s, 1H),7.95 (s, 1H), 7.56 (d, J = 9.5 1-yl)pyridin-2-yl)pyrimidin-2- Hz, 1H),5.13 (dd, J = 14.3, 7.2 Hz, 1H), amine, HCl salt 4.11-3.52 (m, 4H),3.49-3.33 (m, 2H), 3.28-3.06 (m, 2H), 3.00 (s, 3H), 2.88 (s, 3H),2.57-2.34 (m, 2H), 2.18-2.00 (m, 4H), 1.98-1.85 (m, 2H).

Example 14.N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine

Step 1: 7-Prop-1-en-2-ylthieno[3,2-b]pyridine

A mixture of 7-chlorothieno[3,2-b]pyridine (2.0 g, 11.79 mmol),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 g, 17.69mmol), K₃PO₄ (7.5 g, 35.37 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (862.7 mg,1.18 mmol) in 1,4-dioxane (20 mL) and water (6 mL) was bubbled with N₂for 5 min and stirred at 100° C. overnight. LCMS showed the startingmaterial was consumed. The solid was removed by filtration and thefiltrate was concentrated to dryness. The residue was dissolved in EtOAc(50 mL), washed with water (30 mL) and brine (30 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column usingEtOAc/heptanes (0-25%) to afford the title compound (1.71 g, 82.8%yield). LCMS calc. for C₁₀H₁₀NS [M+H]⁺: m/z=176.1; Found: 175.9.

Step 2: 7-Isopropylthieno[3,2-b]pyridine

A mixture of 7-prop-1-en-2-ylthieno[3,2-b]pyridine (1.8 g, 10.15 mmol)and Pd/C (180.0 mg, 0.17 mmol) in methanol (20 mL) was stirred under aH₂ atmosphere overnight. LCMS showed the starting material was consumed.The solid was removed by filtration and the solvent was removed underreduced pressure. The residue was purified by flash chromatography on asilica gel column using EtOAc/heptanes (0-25%) to afford the titlecompound (1.53 g, 84.0% yield). LCMS calc. for C₁₀H₁₂NS [M+H]+:m/z=178.1/179.1; Found: 178.2/179.4.

Step 3: (7-Propan-2-ylthieno[3,2-b]pyridin-2-yl)boronic Acid

To a solution of 7-propan-2-ylthieno[3,2-b]pyridine (300.0 mg, 1.69mmol) in THE (5 mL) at −78° C. was added n-BuLi (0.81 mL, 2.03 mmol)dropwise. The reaction mixture was stirred at −78° C. for 1 h. Then4,4,5,5-tetramethyl-2-propan-2-yloxy-1,3,2-dioxaborolane (629.7 mg, 3.38mmol) was added dropwise. The resulting mixture was stirred from −78° C.to rt overnight. LCMS showed the starting material was consumed. Thereaction was quenched with saturated NH₄Cl solution (5 mL) and extractedwith IPA/CHCl₃ (1:3, 5 mL x 3). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated under reduced pressure to yieldthe title compound as a crude mixture (330 mg), which was used for thenext reaction without further purification.

Step 4:2-(2-Chloro-5-fluoropyrimidin-4-yl)-7-propan-2-ylthieno[3,2-b]pyridine

A mixture of (7-propan-2-ylthieno[3,2-b]pyridin-2-yl)boronic acid (330.0mg, 1.49 mmol), 2,6-dichloro-5-fluororacil (373.8 mg, 2.24 mmol), K₃PO₄(950.5 mg, 4.48 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (109.2 mg,0.15 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was bubbled with N₂for 5 min and stirred at 100° C. overnight. LCMS showed the startingmaterial was consumed. The solvent was removed under reduced pressure.The residue was dissolved in EtOAc (10 mL), washed with water (10 mL)and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column using EtOAc/heptanes (5-60%) to afford the titlecompound (180.0 mg, 39.2% yield). LCMS calc. For C₁₄H₁₁ClFN₃S [M+H]⁺:m/z=308.0; Found: 307.9.

Step 5:N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine

A mixture of2-(2-chloro-5-fluoropyrimidin-4-yl)-7-propan-2-ylthieno[3,2-b]pyridine(18.0 mg, 0.06 mmol), 5-(4-ethylpiperazin-1-yl)pyridin-2-amine (18.1 mg,0.09 mmol), K₃PO₄ (37.2 mg, 0.18 mmol) and XPhos Pd G2 (4.6 mg, 0.01mmol) in 1,4-dioxane (1 mL) was bubbled with N₂ for 5 min and stirred at100° C. overnight. LCMS showed the starting material was consumed. Thesolvent was removed under reduced pressure. The residue was purified byprep-HPLC on a C₁₈ column eluting with MeCN/H₂O (5-100%) with 0.1% TFAto yield title compound as its TFA salt (8.2 mg, 27.2% yield). ¹H NMR(300 MHz, CD₃OD) δ 8.82 (d, J=2.8 Hz, 1H), 8.74 (dd, J=5.1, 2.1 Hz, 1H),8.48 (t, J=2.0 Hz, 1H), 8.20 (dd, J=9.7, 2.6 Hz, 1H), 7.95 (s, 1H), 7.69(d, J=9.5 Hz, 1H), 7.52 (dd, J=5.1, 2.0 Hz, 1H), 3.35 (d, J=1.8 Hz, 1H),3.33-3.32 (m, 8H), 3.31 (s, 2H), 1.52 (d, J=2.1 Hz, 3H), 1.50 (d, J=2.3Hz, 3H), 1.47-1.40 (m, 3H). LCMS calc. for C₂₅H₂₉FN₇S [M+H]⁺:m/z=478.2/479.2; Found: 477.9/479.3.

Example 15.4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1: 2-(6-Nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

A mixture of tert-butyl6-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (500.0mg, 1.56 mmol) and TFA (5.0 mL, 65.34 mmol) in DCM (10 mL) was stirredat room temperature for 2 h. The solvent was removed under reducedpressure. The residue 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane(300 mg, 87.3% yield) was used in the next step without furtherpurification. LC-MS calc. for C₁₀H₁₃N₄O₂ [M+H]⁺: m/z=221.2; Found 220.9.

Step 2: 6-Ethyl-2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane

A mixture of 2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane (500.0mg, 2.27 mmol), triethylamine (0.63 mL, 4.54 mmol), acetic acid (0.01mL, 0.23 mmol), acetaldehyde (500.1 mg, 11.35 mmol), and NaBH₃CN (713.4mg, 11.35 mmol) in methanol (5 mL) was stirred at room temperatureovernight. The solvent was removed under reduced pressure. To theresulting material was added HCl (1 N, 10 mL), and the aqueous mixturewas extracted with ethyl acetate (10 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide the title compound (300 mg, 53.2% yield), which wasdirectly used in the next step without further purification. LC-MS calc.for C₁₂H₁₇N₄O₂ [M+H]⁺: m/z=249.3; Found 249.0.

Step 3: 5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine

A mixture of 6-ethyl-2-(6-nitropyridin-3-yl)-2,6-diazaspiro[3.3]heptane(500.0 mg, 2.01 mmol) and Pd/C (60% H₂O, 50 mg) in ethanol (10 mL) wasstirred under a H₂ atmosphere overnight. The reaction mixture wasfiltered through Celite. The filtrate was concentrated under reducedpressure. The residue was purified by prep-HPLC on a C₁₈ column (30×250mm, 10 m) using mobile phase 0 to 10% MeCN/H₂O (t_(R)=15 min) to affordthe title compound (240 mg, 54.6% yield). LC-MS calc. forC₁₂H₁₉N₄[M+H]⁺: m/z=219.2; Found 218.9.

Step 4:4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 1-5. ¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (s,1H), 8.78 (d, J=3.0 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.30 (s, 1H), 7.96(d, J=9.0 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H), 7.43 (d, J=4.7 Hz, 1H), 7.21(d, J=8.9 Hz, 1H), 4.41-4.31 (m, 2H), 4.27-4.19 (m, 2H), 4.13 (s, 2H),4.03 (s, 2H), 2.20 (m, 3H), 2.05-1.95 (m, 2H), 1.84 (m, 6H). LC-MS calc.for C₂₈H₃₁FN₇S [M+H]⁺: m/z=516.2/517.2; Found 516.2/517.2.

Example 16.4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1: 7-(Cyclopenten-1-yl)thieno[3,2-b]pyridine

A mixture of 7-chlorothieno[3,2-b]pyridine (1.02 g, 6.01 mmol),2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 g,9.02 mmol), K₃PO₄ (3.83 g, 18.04 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (439.98 mg,0.60 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was bubbled with N₂for 5 min and stirred at 100° C. overnight. LCMS showed the startingmaterial was consumed. The solvent was removed under reduced pressure.The residue was dissolved in EtOAc (20 mL), washed with water (20 mL)and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column using EtOAc/heptanes (0-20%) to afford the titlecompound (1.1 g, 91% yield) as a colorless oil. LC-MS calc. for C₁₂H₁₂NS[M+H]⁺: m/z=202.0; Found 201.9.

Step 2: 7-Cyclopentylthieno[3,2-b]pyridine

A mixture of 7-(cyclopenten-1-yl)thieno[3,2-b]pyridine (1.1 g, 5.46mmol) and Pd/C (10 wt % Pd, 200.0 mg, 0.19 mmol) in methanol (20 mL) wasstirred under a H₂ atmosphere overnight. LCMS showed the startingmaterial was consumed. The solid was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on a silica gel column usingEtOAc/heptanes (0-20%) to afford the title compound (1.0 g, 90.0% yield)as a colorless oil. LC-MS calc. for C₁₂H₁₄NS [M+H]⁺: m/z=204.0; Found203.9.

Step 3: 3-Chloro-7-cyclopentylthieno[3,2-b]pyridine

A mixture of 7-cyclopentylthieno[3,2-b]pyridine (300.0 mg, 1.48 mmol)and 1-chloropyrrolidine-2,5-dione (236.46 mg, 1.77 mmol) intrifluoromethanesulfonic acid (1.0 mL, 11.33 mmol) was stirred at roomtemperature overnight. LCMS showed the starting material was consumed.The mixture was poured into cold NaHCO₃ solution (10 mL) and extractedwith EtOAc (10 mL×3). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column usingEtOAc/heptanes (0-20%) to afford the title compound as a mixture withthe dichloro compound (276 mg, 78.7% yield, 3:1 ratio by HPLC). LCMScalc. for C₁₂H₁₃ClNS [M+H]⁺: m/z=238.05/240.04; Found: 238.3/240.0.

Step 4:4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. ¹H NMR (300 MHz, CD₃OD) δ 8.93 (d,J=2.2 Hz, 1H), 8.78 (d, J=4.9 Hz, 1H), 8.32-8.22 (m, 1H), 7.94 (s, 1H),7.64-7.54 (m, 2H), 3.96 (d, J=9.4 Hz, 2H), 3.75 (s, 2H), 3.50-3.43 (m,1H), 3.32 (m, 6H), 2.30 (d, J=8.8 Hz, 2H), 2.01-1.81 (m, 6H), 1.44 (t,J=7.2 Hz, 3H). LCMS calc. for C₂₇H₃₀ClFN₇S [M+H]: m/z=538.2/540.2;Found: 538.1/540.3.

Example 17.2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol

Step 1: 1-Thieno[3,2-b]pyridin-7-ylethanone

A mixture of 7-chlorothieno[3,2-b]pyridine (1.21 g, 7.13 mmol),tributyl(1-ethoxyvinyl)tin (3.61 mL, 10.7 mmol), andtetrakis(triphenylphosphine)palladium(0) (824 mg, 0.713 mmol) in1,4-dioxane (25 mL) was stirred at 100° C. for 16 h. The reactionmixture was cooled to room temperature, and 2N HCl (aq.) (10 mL) wasadded. The mixture was further stirred overnight. The mixture wasneutralized with sat. NaHCO₃ (aq.) (10 mL) and extracted with EtOAc (25mL×3). The combined organic layers were washed with water (25 mL) andbrine (25 mL), dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography (0-50% EtOAc/heptane)to give the title compound (601 mg, 3.39 mmol, 47.5% yield) as a whitesolid. LCMS calc. for C₉H₈NOS [M+H]⁺: m/z=178.0; Found: 178.1.

Step 2: 2-Thieno[3,2-b]pyridin-7-ylpropan-2-ol

A mixture of methylmagnesium chloride solution (0.86 mL, 2.59 mmol) and1-thieno[3,2-b]pyridin-7-ylethanone (153.0 mg, 0.86 mmol) in THF (2 mL)was stirred at room temperature for 2 h. LCMS showed the startingmaterial was consumed. The reaction was quenched with saturated NH₄Clsolution (5 mL) and extracted with EtOAc (5 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column using EtOAc/heptanes (5-50%) to afford the title compound(112.0 mg, 67.1% yield). LCMS calc. for C₁₀H₁₂NOS [M+H]″ m/z=194.0;Found: 193.9.

Step 3:2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. LCMS calc. for C₂₅H₂₉FN₇OS [M+H]⁺:m/z=494.2/495.2; Found: 494.0/495.4.

Example 18.2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol

Step 1: 1,1,1-Trifluoro-2-thieno[3,2-b]pyridin-7-ylpropan-2-ol

To a solution of 1-thieno[3,2-b]pyridin-7-ylethanone (88.0 mg, 0.50mmol) in THE (2 mL) was added tetrabutylammonium fluoride solution (0.1mL, 0.10 mmol), followed by the addition oftrimethyl(trifluoromethyl)silane (91.8 mg, 0.65 mmol) dropwise at 0° C.The reaction mixture was stirred at 0° C. for 5 min and room temperaturefor 2 h. The mixture was cooled to 0° C. and tetrabutylammonium fluoridesolution (0.1 mL, 0.10 mmol) and water (0.1 mL, 5.55 mmol) were added.The resulting mixture was stirred at room temperature for 30 min. LCMSshowed the starting material was consumed. The reaction was quenchedwith brine (5 mL) and extracted with EtOAc (5 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column using EtOAc/heptanes (5-50%) to afford the titlecompound (80.0 mg, 65.2% yield). LCMS calc. for C₁₀H₉F₃NOS [M+H]⁺:m/z=248.04/249.04; Found: 248.1/249.3.

Step 2:2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. ¹H NMR (300 MHz, CD₃OD) δ 8.75 (t,J=4.2 Hz, 2H), 8.41 (d, J=1.8 Hz, 1H), 7.64 (dd, J=9.4, 2.8 Hz, 1H),7.58-7.51 (m, 2H), 7.47 (d, J=2.7 Hz, 1H), 4.51 (d, J=11.2 Hz, 2H), 4.30(d, J=14.6 Hz, 4H), 4.18 (s, 2H), 3.25 (d, J=7.1 Hz, 2H), 1.94 (s, 3H),1.23 (t, J=7.2 Hz, 3H). LCMS calc. for C₂₆H₂₆F₄N₇OS [M+H]⁺:m/z=560.2/561.2; Found: 560.0/561.3.

Examples listed in Table 2-1 and 2-2 are synthesized according toprocedures analogous to Example 14 (Method 1), Example 15 (Method 2),Example 16 (Method 3), Example 17 (Method 4), or Example 18 (Method 5).

TABLE 2-1 Examples 19-41 Example R₁ R₂ R₃ LCMS [M + H]⁺ Method 19 Hisopropyl

491.9 1 20 Cl cyclopentyl

537.1 3 21 H

560.0 4 22 Me cyclopentyl

532.3 1 23 H isopropyl

490.0 2 24 H cyclopentyl

504.2 1 25 H

562.0 5 26 Me cyclopentyl

502.9 1 27 H

507.9 4 28 Me cyclopentyl

503.9 1 29 H

547.9 5 30 Cl cyclopentyl

552.2 3 31 Me cyclopentyl

518.0 1 32 Me cyclopentyl

501.9 2 33 H cyclopentyl

518.2 1 34 H cyclopentyl

489.0 1 35 Me cyclopentyl

489.8 1 36 H cyclopentyl

476.1 1 37 H cyclopentyl

490.1 1 38 Me cyclopentyl

490.9 1 39 H cyclopentyl

504.9 1 40 H cyclopentyl

476.9 1 41 H cyclopentyl

496.9 1

TABLE 2-2 Examples 19-41 Example Compound name NMR 19N-[5-[(4-Ethylpiperazin-1- ¹H NMR (300 MHz, CD₃OD) δ 8.89 (d, J = 3.0yl)methyl]pyridin-2-yl]-5- Hz, 1H), 8.79 (d, J = 5.2 Hz, 1H), 8.51 (d, J= fluoro-4-(7-propan-2- 1.5 Hz, 1H), 8.35 (dd, J = 7.0, 2.2 Hz, 2H),ylthieno[3,2-b]pyridin-2- 7.68 (d, J = 9.6 Hz, 1H), 7.60 (d, J = 5.2 Hz,yl)pyrimidin-2-amine 1H), 3.78 (s, 2H), 3.46-3.40 (m, 1H), 3.31 (m, 8H),3.24 (dd, J = 7.4, 1.7 Hz, 2H), 1.52 (dd, J = 7.0, 1.8 Hz, 6H), 1.37 (t,J = 7.3 Hz, 3H). 20 4-(3-Chloro-7- ¹H NMR (300 MHz, Methanol-d₄) δ 8.99(t, J = cyclopentylthieno[3,2- 1.8 Hz, 1H), 8.80 (d, J = 5.0 Hz, 1H),8.44- b]pyridin-2-yl)-N-[5-(1- 8.30 (m, 2H), 7.68-7.55 (m, 2H), 3.75 (d,J = ethylpiperidin-4-yl)pyridin-2- 12.5 Hz, 2H), 3.49 (t, J = 7.4 Hz,1H), 3.27 (d, yl]-5-fluoropyrimidin-2- J = 7.5 Hz, 2H), 3.16 (s, 2H),2.34-1.81 (m, amine 13H), 1.43 (t, J = 7.3 Hz, 3H) 212-[2-[2-[[5-(6-Ethyl-2,6- ¹H NMR (300 MHz, CD₃OD) δ 8.78 (d, J = 3.1diazaspiro[3.3]heptan-2- Hz, 1H), 8.71 (d, J = 5.1 Hz, 1H), 8.43 (d, J =yl)pyridin-2-yl]amino]-5- 1.8 Hz, 1H), 7.67 (dd, J = 9.4, 2.8 Hz, 1H),fluoropyrimidin-4- 7.55-7.47 (m, 3H), 4.51 (d, J = 11.2 Hz, 2H),yl]thieno[3,2-b]pyridin-7- 4.31 (d, J = 12.3 Hz, 4H), 4.19 (s, 2H), 3.27(d, yl]propan-2-ol J = 7.3 Hz, 2H), 1.72 (s, 6H), 1.23 (t, J = 7.2 Hz,3H). 22 4-(7-Cyclopentyl-3- ¹H NMR (300 MHz, CD₃OD) δ 8.89 (d, J = 2.4methylthieno[3,2-b]pyridin-2- Hz, 1H), 8.74 (d, J = 5.2 Hz, 1H), 8.32(d, J = yl)-N-(5-((4-ethylpiperazin-1- 6.7 Hz, 2H), 7.60 (dd, J = 19.4,7.4 Hz, 2H), yl)methyl)pyridin-2-yl)-5- 3.74 (s, 2H), 3.59-3.32 (m, 4H),3.21 (dd, J = fluoropyrimidin-2-amine 14.7, 7.3 Hz, 4H), 2.75 (d, J =3.0 Hz, 3H), 2.36-2.22 (m, 2H), 2.00-1.78 (m, 6H), 1.34 (t, J = 7.3 Hz,3H). 23 N-[5-(6-Ethyl-2,6- ¹H NMR (300 MHz, CD₃OD) δ 8.83 (d, J = 3.0diazaspiro[3.3]heptan-2- Hz, 1H), 8.77 (d, J = 5.1 Hz, 1H), 8.48 (d, J =yl)pyridin-2-yl]-5-fluoro-4-(7- 1.5 Hz, 1H), 7.71 (dd, J = 9.5, 2.8 Hz,1H), propan-2-ylthieno[3,2- 7.60-7.52 (m, 2H), 7.53-7.49 (m, 1H), 4.53b]pyridin-2-yl)pyrimidin-2- (d, J = 11.4 Hz, 2H), 4.33 (d, J = 12.0 Hz,4H), amine 4.21 (s, 2H), 3.41 (t, J = 6.9 Hz, 1H), 3.30- 3.24 (m, 2H),1.54 (s, 3H), 1.51 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 244-(7-Cyclopentylthieno[3,2- ¹H NMR (300 MHz, DMSO-d₆) δ 10.57 (s,b]pyridin-2-yl)-N-[5-(4- 1H), 8.80 (d, J = 2.9 Hz, 1H), 8.69 (d, J = 4.6ethylpiperazin-1-yl)pyridin-2- Hz, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.99(d, J = yl]-5-fluoropyrimidin-2- 9.2 Hz, 1H), 7.78 (d, J = 9.3 Hz, 1H),7.41 (d, J = amine 4.7 Hz, 1H), 3.86 (d, J = 11.9 Hz, 2H), 3.62 (d, J =10.9 Hz, 2H), 3.27-2.99 (m, 7H), 2.17 (s, 2H), 1.80 (d, J = 5.1 Hz, 6H),1.24 (dd, J = 14.8, 7.6 Hz, 3H). 25 2-[2-[2-[[5-[(4- ¹H NMR (300 MHz,CD₃OD) δ 8.85 (d, J = 3.0 Ethylpiperazin-1- Hz, 1H), 8.77 (d, J = 5.0Hz, 1H), 8.45 (d, J = yl)methyl]pyridin-2- 1.8 Hz, 1H), 8.36-8.29 (m,2H), 7.66 (d, J = yl]amino]-5-fluoropyrimidin- 9.6 Hz, 1H), 7.58 (d, J =4.9 Hz, 1H), 3.75 (s, 4-yl]thieno[3,2-b]pyridin-7- 2H), 3.55 (s, 2H),3.34-3.31 (m, 6H), 3.24 (d, yl]-1,1,1-trifluoropropan-2-ol J = 7.3 Hz,2H), 1.95 (s, 3H), 1.36 (t, J = 7.3 Hz, 3H). 26 4-(7-Cyclopentyl-3- —methylthieno[3,2-b]pyridin-2- yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin- 2-yl)pyrimidin-2-amine 272-[2-[2-[[5-[(4-Ethylpiperazin- ¹H NMR (300 MHz, CD₃OD) δ 8.87-8.83 (m,1-yl)methyl]pyridin- 1H), 8.75-8.71 (m, 1H), 8.45 (d, J = 1.8 Hz,2-yl]amino]-5-fluoropyrimidin- 1H), 8.36-8.29 (m, 2H), 7.70-7.64 (m,1H), 4-yl]thieno[3,2-b]pyridin-7- 7.54 (dd, J = 5.2, 1.8 Hz, 1H), 3.75(s, 2H), yl]propan-2-ol 3.30 (m, 8H), 3.25-3.20 (m, 2H), 1.73 (s, 6H),1.38-1.32 (m, 3H). 28 4-(7-Cyclopentyl-3- ¹H NMR (300 MHz, CD₃OD) δ 8.84(d, J = 2.5 methylthieno[3,2-b]pyridin-2- Hz, 1H), 8.74 (d, J = 5.2 Hz,1H), 8.22 (dd, J = yl)-5-fluoro-N-(5-(4- 9.7, 2.9 Hz, 1H), 7.90 (d, J =2.8 Hz, 1H), 7.58 methylpiperazin-1-yl)pyridin- (dd, J = 7.4, 4.7 Hz,2H), 4.08-3.30 (m, 8H), 2-yl)pyrimidin-2-amine 3.24-3.20 (m, 1H), 2.98(s, 3H), 2.74 (d, J = 3.0 Hz, 3H), 2.38-2.21 (m, 2H), 1.99-1.74 (m, 6H).29 2-[2-[2-[[5-(4-Ethylpiperazin- ¹H NMR (300 MHz, CD₃OD) δ 8.81 (d, J =3.2 1-yl)pyridin-2-yl]amino]-5- Hz, 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.43(d, J = fluoropyrimidin-4- 1.8 Hz, 1H), 8.22 (dd, J = 9.6, 2.9 Hz, 1H),yl]thieno[3,2-b]pyridin-7-yl]- 7.91 (d, J = 2.9 Hz, 1H), 7.62 (d, J =9.6 Hz, 1,1,1-trifluoropropan-2-ol 1H), 7.57 (d, J = 5.1 Hz, 1H), 3.67(d, J = 1.3 Hz, 2H), 3.37-3.31 (m, 8H), 1.94 (s, 3H), 1.43 (t, J = 7.4Hz, 3H). 30 4-(3-Chloro-7- — cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4- ethylpiperazin-1- yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine 31 4-(7-Cyclopentyl-3- ¹H NMR (300 MHz, CD₃OD) δ8.84 (d, J = 2.0 methylthieno[3,2-b]pyridin-2- Hz, 1H), 8.72 (d, J = 5.1Hz, 1H), 8.22 (dd, J = yl)-N-(5-(4-ethylpiperazin-1- 9.6, 2.3 Hz, 1H),7.91 (s, 1H), 7.56 (dd, J = yl)pyridin-2-yl)-5- 13.8, 7.4 Hz, 2H),4.15-3.10 (m, 11H), 2.73 fluoropyrimidin-2-amine (d, J = 2.8 Hz, 3H),2.31-2.21 (m, 2H), 1.94- 1.81 (m, 6H), 1.39 (t, J = 7.3 Hz, 3H). 32N-(5-(2,6- ¹H NMR (300 MHz, CD₃OD) δ 8.60 (d, J = 2.5Diazaspiro[3.3]heptan-2- Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.46 (dd, J= yl)pyridin-2-yl)-4-(7- 9.4, 2.7 Hz, 1H), 7.32 (s, 1H), 7.28 (s, 2H),cyclopentyl-3- 4.13 (s, 4H), 4.01 (s, 4H), 3.26-3.21 (m, 1H),methylthieno[3,2-b]pyridin-2- 2.53 (d, J = 2.9 Hz, 3H), 2.15-2.00 (m,2H), yl)-5-fluoropyrimidin-2- 1.79-1.63 (m, 6H). amine 334-(7-Cyclopentylthieno[3,2- ¹H NMR (300 MHz, DMSO-d₆) δ 10.83 (s,b]pyridin-2-yl)-N-[5-[(4- 1H), 8.85 (d, J = 3.0 Hz, 1H), 8.70 (d, J =4.9 ethylpiperazin-1- Hz, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.20 (d, J =yl)methyl]pyridin-2-yl]-5- 8.7 Hz, 1H), 7.98 (dd, J = 8.8, 1.9 Hz, 1H),fluoropyrimidin-2-amine 7.42 (d, J = 4.9 Hz, 1H), 4.06 (s, 2H),3.70-2.75 (m 11H), 2.26-2.10 (m, 2H), 1.90-1.69 (m, 6H), 1.20 (t, J =7.2 Hz, 3H). 34 4-(7-Cyclopentylthieno[3,2- ¹H NMR (300 MHz, DMSO-d₆) δ10.41 (s, b]pyridin-2-yl)-5-fluoro-N-(5- 1H), 9.49 (s, 1H), 8.83 (d, J =3.0 Hz, 1H), 8.70 (1-methylpiperidin-4- (d, J = 4.8 Hz, 1H), 8.30 (d, J= 1.6 Hz, 1H), yl)pyridin-2-yl)pyrimidin-2- 8.24 (d, J = 2.0 Hz, 1H),8.18 (d, J = 8.7 Hz, amine 1H), 7.78 (dd, J = 8.7, 2.2 Hz, 1H), 7.42 (d,J = 4.8 Hz, 1H), 3.09 (dd, J = 22.5, 10.3 Hz, 4H), 2.97-2.78 (m, 5H),2.30-2.13 (m, 2H), 2.13- 2.00 (m, 2H), 1.97-1.69 (m, 8H). 354-(7-Cyclopentyl-3- ¹H NMR (300 MHz, CD₃OD) δ 8.83 (s, 1H),methylthieno[3,2-b]pyridin-2- 8.71 (d, J = 5.1 Hz, 1H), 8.22 (d, J = 9.7Hz, yl)-5-fluoro-N-(5-(piperazin- 1H), 7.90 (s, 1H), 7.59 (d, J = 9.4Hz, 1H), 7.52 1-yl)pyridin-2-yl)pyrimidin-2- (d, J = 5.1 Hz, 1H),3.55-3.42 (m, 8H), 3.24- amine 3.15 (m, 1H), 2.73 (d, J = 2.7 Hz, 3H),2.38- 2.22 (m, 2H), 2.00-1.78 (m, 6H). 36 4-(7-Cyclopentylthieno[3,2- ¹HNMR (300 MHz, DMSO-d₆) δ 10.65 (s, b]pyridin-2-yl)-5-fluoro-N-(5- 1H),8.84 (d, J = 2.9 Hz, 1H), 8.73 (d, J = 4.8 piperazin-1-ylpyridin-2- Hz,1H), 8.33 (s, 1H), 8.06 (d, J = 2.7 Hz, 1H), yl)pyrimidin-2-amine 8.00(d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.45 (d, J = 4.8 Hz, 1H),3.43-3.26 (m, 9H), 2.20 (s, 2H), 1.83 (m, 6H). 374-(7-Cyclopentylthieno[3,2- ¹H NMR (300 MHz, DMSO-d₆) δ 10.69 (s,b]pyridin-2-yl)-5-fluoro-N-[5- 1H), 8.81 (d, J = 3.0 Hz, 1H), 8.70 (d, J= 4.8 (4-methylpiperazin-1- Hz, 1H), 8.30 (s, 1H), 8.05 (d, J = 2.7 Hz,1H), yl)pyridin-2-yl]pyrimidin-2- 7.96 (d, J = 9.3 Hz, 1H), 7.81 (dd, J= 9.3, 2.7 amine Hz, 1H), 7.42 (d, J = 4.9 Hz, 1H), 3.85 (d, J = 11.4Hz, 2H), 3.54 (s, 2H), 3.45-3.30 (m, 1H), 3.20 (s, 2H), 3.05 (d, J =11.9 Hz, 2H), 2.87 (s, 3H), 2.19 (d, J = 8.3 Hz, 2H), 1.92-1.68 (m, 6H).38 4-(7-Cyclopentyl-3- ¹H NMR (300 MHz, CD₃OD) δ 8.65 (d, J = 2.4methylthieno[3,2-b]pyridin-2- Hz, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7.99(dd, J = yl)-5-fluoro-N-(5- 92, 2.8 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H),7.39 morpholinopyridin-2- (d, J = 5.2 Hz, 1H), 7.32 (d, J = 9.7 Hz, 1H),yl)pyrimidin-2-amine 3.66 (t, 4H), 3.35-3.24 (m, 1H), 3.03 (t, 4H), 2.55(d, J = 3.0 Hz, 3H), 2.14-2.04 (m, 2H), 1.78-1.63 (m, 6H). 394-(7-Cyclopentylthieno[3,2- — b]pyridin-2-yl)-5-fluoro-N-[5-(4-methoxypiperidin-1- yl)pyridin-2-yl]pyrimidin-2- amine 404-(7-Cyclopentylthieno[3,2- ¹H NMR (300 MHz, CDCl3) δ 12.55 (s, 1H),b]pyridin-2-yl)-5-fluoro-N-(5- 9.05 (s, 1H), 8.91 (d, J = 9.8 Hz, 1H),8.79 (d, J = morpholinopyridin-2- 5.7 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H),8.16 yl)pyrimidin-2-amine (dd, J = 10.0, 2.5 Hz, 1H), 7.66 (d, J = 2.9Hz, 1H), 7.59 (d, J = 5.6 Hz, 1H), 3.97-3.89 (m, 4H), 3.59 (d, J = 8.1Hz, 1H), 3.29-3.17 (m, 4H), 2.40 (s, 2H), 2.14-1.78 (m, 6H). 414-(7-Cyclopentylthieno[3,2- — b]pyridin-2-yl)-N-[5-(3,3-difluoropyrrolidin-1- yl)pyridin-2-yl]-5- fluoropyrimidin-2-amine

Example 42.4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine

Step 1: 4-(Cyclopenten-1-yl)thieno[2,3-b]pyri dine

A mixture of 4-chlorothieno[2,3-b]pyridine (696.0 mg, 4.10 mmol),2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1194.5 mg,6.15 mmol), K₃PO₄ (2612.8 mg, 12.31 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (300.2 mg,0.41 mmol) in 1,4-dioxane (8 mL) and H₂O (2 mL) was bubbled with N₂ for5 min and stirred at 100° C. for 6 h. LCMS showed the starting materialwas consumed. The solvent was removed under reduced pressure. Theresidue was dissolved in EtOAc (20 mL), washed with water (20 mL) andbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography on asilica gel column using EtOAc/heptanes (0-20%) to afford the titlecompound (775.0 mg, 93.8% yield). LCMS calc. for C₁₂H₁₂NS [M+H]⁺:m/z=202.1; Found: 201.9.

Step 2: 4-Cyclopentylthieno[2,3-b]pyridine

A mixture of 4-(cyclopenten-1-yl)thieno[2,3-b]pyridine (930.0 mg, 4.62mmol) and Pd/C (10 wt % Pd, 180.0 mg, 0.17 mmol) in methanol (30 mL) andacetic acid (3 mL) was stirred under a H₂ atmosphere for 24 h. Thereaction mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was dissolved in EtOAc (20 mL), washedwith saturated NaHCO₃ solution (20 mL) and brine (20 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by flash chromatography on a silica gel column usingEtOAc/heptanes (0-15%) to afford the title compound (565.0 mg, 60.2%yield). LCMS calc. for C₁₂H₁₄NS [M+H]⁺: m/z=204.1; Found: 203.9.

Step 3:4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. ¹H NMR (300 MHz, CD₃OD) δ 8.77 (d,J=3.3 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.45 (s, 1H), 8.18 (dd, J=9.7,2.9 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H), 7.54 (d, J=9.6 Hz, 1H), 7.44 (d,J=5.0 Hz, 1H), 3.94-3.84 (m, 4H), 3.73-3.63 (m, 1H), 3.27-3.22 (m, 4H),2.33-2.18 (m, 2H), 1.98-1.78 (m, 6H). LCMS calc. for C₂₅H₂₆FN₆OS [M+H]⁺:m/z=477.2/478.2; Found: 477.0/478.3.

Examples listed in Table 3-1 and 3-2 are synthesized according toprocedures analogous to Example 42.

TABLE 3-1 Examples 43-47 Example R₃ LCMS [M + H]⁺ 43

489.0 44

504.0 45

490.0 46

476.0 47

516.0

TABLE 3-2 Examples 43-47 Example Compound name NMR 43 4-(4- ¹H NMR (300MHz, CD₃OD) δ 8.77 Cyclopentylthieno[2,3- (dd, J = 14.1, 3.2 Hz, 1H),8.59 (dd, J = b]pyridin-2-yl)-5- 5.0, 2.6 Hz, 1H), 8.47 (d, J = 11.0 Hz,fluoro-N-(5-(1- 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.24- methylpiperidin-4-8.05 (m, 1H), 7.83 (d, J = 9.0 Hz, 1H), yl)pyridin-2- 7.46 (dd, J = 5.0,2.4 Hz, 1H), 3.70 (d, J = yl)pyrimidin-2-amine 10.3 Hz, 2H), 3.27 (s,1H), 3.27- 3.13 (m, 2H), 3.07 (s, 1H), 2.98 (s, 3H), 2.40-2.13 (m, 3H),2.13-1.61 (m, 7H), 1.45-1.33 (m, 2H). 44 4-(4- ¹H NMR (300 MHz, CD₃OD) δ8.74 Cyclopentylthieno[2,3- (d, J = 3.2 Hz, 1H), 8.55 (d, J = 5.0 Hz,b]pyridin-2-yl)-N-[5- 1H), 8.42 (s, 1H), 8.23-8.15 (m, 1H),(4-ethylpiperazin-1- 7.93 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 9.6yl)pyridin-2-yl]-5- Hz, 1H), 7.42 (d, J = 5.0 Hz, 1H), 3.74-fluoropyrimidin-2- 3.62 (m, 3H), 3.57 (s, 2H), 3.33-3.27 amine (m, 6H),2.29-2.19 (m, 2H), 1.96- 1.81 (m, 6H), 1.43 (t, J = 7.3 Hz, 3H). 454-(4- ¹H NMR (300 MHz, CD₃OD) δ 8.80 (d, Cyclopentylthieno[2,3- J = 3.3Hz, 1H), 8.58 (d, J = 5.0 Hz, b]pyridin-2-yl)-5- 1H), 8.48 (s, 1H), 8.27(dd, J = 9.7, 2.9 fluoro-N-[5-(4- Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H),7.58 methylpiperazin-1- (d, J = 9.6 Hz, 1H), 7.46 (d, J = 5.0 Hz,yl)pyridin-2- 1H), 3.94 (s, 2H), 3.80-3.63 (m, 3H), yl]pyrimidin-2-amine3.34 (m, 4H), 3.03 (s, 3H), 2.40-2.12 (m, 2H), 2.02-1.76 (m, 6H). 464-(4- ¹H NMR (300 MHz, CD₃OD) δ 8.77 Cyclopentylthieno[2,3- (d, J = 3.2Hz, 1H), 8.57 (d, J = 5.0 Hz, b]pyridin-2-yl)-5- 1H), 8.45 (s, 1H), 8.26(dd, J = 9.7, 2.9 fluoro-N-(5-piperazin- Hz, 1H), 7.92 (d, J = 2.7 Hz,1H), 7.56 1-ylpyridin-2- (d, J = 9.6 Hz, 1H), 7.44 (d, J = 5.1 Hz,yl)pyrimidin-2-amine 1H), 3.72-3.64 (m, 1H), 3.58-3.52 (m, 4H),3.50-3.45 (m, 4H), 2.33- 2.19 (m, 2H), 1.96-1.76 (m, 6H). 47 4-(4- ¹HNMR (300 MHz, DMSO-d₆) δ 10.24 Cyclopentylthieno[2,3- (s, 1H), 8.78 (d,J = 3.0 Hz, 1H), 8.71 b]pyridin-2-yl)-N-[5- (d, J = 4.8 Hz, 1H), 8.30(s, 1H), 7.96 (6-ethyl-2,6- (d, J = 9.0 Hz, 1H), 7.64 (d, J = 2.5 Hz,diazaspiro[3.3]heptan- 1H), 7.43 (d, J = 4.7 Hz, 1H), 7.21 (d, J =2-yl)pyridin-2-yl]-5- 8.9 Hz, 1H), 4.41-4.31 (m, 2H), 4.27-fluoropyrimidin-2- 4.19 (m, 2H), 4.13 (s, 2H), 4.03 (s, amine 2H), 2.20(m, 3H), 2.05-1.95 (m, 2H), 1.84 (m, 6H).

Example 48.4-(7-Cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine

Step 1. 4-Methylthiophene-2-carbonyl Chloride

Oxalyl chloride (2.631 g, 1.778 mL, 20.7 mmol, 1.25 equiv.) was addeddropwise into the solution of 4-methylthiophene-2-carboxylic acid (2.358g, 16.6 mmol, 1.00 equiv.) in DMF (61 mg, 64 μL, 0.83 mmol, 0.05 equiv.)at 0° C. The resulting light green solution was allowed to warm toambient temperature and stirred for 4 h, when LC-MS analysis (quenchedwith morpholine) indicated the complete consumption of the carboxylicacid. The reaction mixture was concentrated under reduced pressure anddried under high vacuum. The crude acid chloride was used directlywithout further purification.

Step 2. N-Hydroxy-4-methylthiophene-2-carboxamide

The solution of crude 4-methylthiophene-2-carbonyl chloride from Step 1in THE (10 mL) was added dropwise into the suspension of NH₂OH HCl(4.615 g, 66.4 mmol, 4.00 equiv.) and NaOH (3.320 g, 83.0 mmol, 5.00equiv.) in THE (10 mL) and H₂O (20 mL) at 0° C. The resulting mixturewas slowly warmed to ambient temperature and stirred for another 2 h.The reaction mixture was acidified with 2 N HCl (pH 3) and extractedwith EtOAc (30 mL×3). The combined organic layer was washed withsaturated NaHCO₃ solution (30 mL), H₂O (30 mL) and brine (30 mL), driedover anhydrous Na₂SO₄, filtered, and evaporated in vacuo. The crudeproduct obtained as yellow solid, was used in the next step withoutfurther purification. LCMS calc. for C₆H₈NO₂S [M+H]⁺: m/z=158.0; Found:158.1.

Step 3. 4-Methyl-N-(pivaloyloxy)thiophene-2-carboxamide

Trimethylacetyl chloride (1.951 g, 16.6 mmol, 1.00 equiv.) was addeddropwise into the solution of crudeN-hydroxy-4-methylthiophene-2-carboxamide (from Step 2) and Et₃N (2.016g, 2.777 mL, 19.9 mmol, 1.20 equiv.) in THE (25 mL) at 0° C. Theresulting orange suspension was warmed to ambient temperature andstirred for 18 h. The light-yellow milky reaction mixture wasconcentrated to ⅓ of its original volume and partitioned between H₂O (30mL) and EtOAc (30 mL). The organic phase was separated and the aqueousphase extracted with EtOAc (20 mL×3). The combined organic phase waswashed with H₂O (30 mL) and brine (30 mL), dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (5%-20% EtOAc, 10% DCM in heptanes) to givethe title compound (3.732 g, 15.5 mmol, 93.2% yield for three steps) aswhite solid. R_(f)=0.4 (30% EtOAc in heptanes). LCMS calc. forC₁₁H₁₆NO₃S [M+H]⁺: m/z=242.1; Found: 242.0.

Step 4. 3-Methylthieno[2,3-c]pyridin-7(6H)-one

The suspension of [(4-methylthiophene-2-carbonyl)amino]2,2-dimethylpropanoate (1.316 g, 5.45 mmol, 1.00 equiv.), CsOAc (1.050g, 5.45 mmol, 1.00 equiv.), [Cp*RhCl₂]₂(101 mg, 0.16 mmol, 0.03 equiv.),and vinyl acetate (704 mg, 8.18 mmol, 1.50 equiv.) in anhydrous MeOH (15mL) was stirred at 45° C. under a N₂ atmosphere for 18 h. The reactionwas diluted with H₂O (30 mL) and extracted with EtOAc (20 mL×3). Thecombined organic phase was washed with H₂O (20 mL) and brine (20 mL),dried over Na₂SO₄, filtered, and evaporated under reduced pressure. Theresidue was purified by flash chromatography on silica gel column (0-50%EtOAc in heptanes containing 0.1% Et₃N) to give the title compound (527mg, 3.19 mmol, 58.5% yield) as salmon solid. R_(f)=0.25 (50% EtOAc inheptanes). LCMS calc. for C₈H₈NOS [M+H]⁺: m/z=166.0; Found: 166.1.

Step 5. 7-Chloro-3-methylthieno[2,3-c]pyridine

The mixture of 3-methyl-6H-thieno[2,3-c]pyridin-7-one (527 mg, 3.19mmol, 1.00 equiv.) and POCl₃ (2.935 mg, 19.1 mmol, 6.00 equiv.) washeated at 100° C. for 3 h, when LCMS indicated the complete consumptionof the starting material. The excess POCl₃ was evaporated under reducedpressure and the residue was partitioned between 10% Na₂CO₃ (20 mL)solution and EtOAc (10 mL). The organic layer was separated, and theaqueous layer extracted with EtOAc (10 mL×3). The combined organic phasewas washed with 10% Na₂CO₃ solution (10 mL), H₂O (10 mL) and brine (10mL), dried over Na₂SO₄, filtered and evaporated under reduced pressure.The oily residue was purified by flash chromatography on a silica gelcolumn (0-50% EtOAc in heptanes) to give the title compound (332 mg,1.81 mmol, 56.7% yield) as a yellow solid. R_(f)=0.3 (50% EtOAc inheptanes). LCMS calc. for C₈H₇ClNS [M+H]⁺: m/z=184.0; Found: 184.1.

Step 6. 7-(Cyclopent-1-en-1-yl)-3-methylthieno[2,3-c]pyridine

The suspension of 7-chloro-3-methylthieno[2,3-c]pyridine (332 mg, 1.81mmol, 1.00 equiv.),2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (526 mg,2.71 mmol, 1.50 equiv.), Pd(dppf)Cl₂ (66 mg, 0.09 mmol, 0.05 equiv.),and K₃PO₄ (1.535 g, 7.23 mmol, 4.00 equiv.) in 1,4-dioxane (8 mL) andH₂O (2 mL) was stirred at 100° C. under nitrogen atmosphere for 18 h.The reaction mixture was cooled to ambient temperature and thenpartitioned between H₂O (30 mL) and EtOAc (15 mL). The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (15 mL×3). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered, andevaporated in vacuo. The residue was purified by flash chromatography onsilica gel column (0-25% MTBE in heptanes) to give the title compound(308 mg, 1.43 mmol, 79.0% yield) as colorless oil. R_(f)=0.4 (30% MTBEin heptanes). LCMS calc. for C₁₃H₁₄NS [M+H]⁺: m/z=216.1; Found: 216.0.

Step 7. 7-Cyclopentyl-3-methylthieno[2,3-c]pyridine

The solution of 7-(cyclopenten-1-yl)-3-methylthieno[2,3-c]pyridine (308mg, 1.43 mmol) in MeOH (5 mL) was cooled at 0° C. Pd/C (10 wt % Pd, 31mg, 0.29 mmol) was added and the reaction flask was evacuated andflushed with hydrogen gas. The reaction mixture was allowed to warm toroom temperature and stirred for 4 h. The solid materials were filteredoff through a pad of Celite and the filter cake was washed with MeOH (5mL×2). The combined filtrate was concentrated under reduced pressure andthe residue was purified by flash chromatography on silica gel column(0-25% MTBE in heptanes) to give the title compound (305 mg, 1.40 mmol,98.1% yield) as light yellow solid. R_(f)=0.3 (25% MTBE in heptanes).LCMS calc. for C₁₃H₁₆NS [M+H]⁺: m/z=218.1; Found: 218.0.

Step 8.4-(7-Cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. LCMS calc. for C₂₇H₃₁FN₇S [M+H]⁺:m/z=504.2; Found: 504.0.

Example 49.4-(4-Cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

Step 1: 4-(Cyclopent-1-en-1-yl)-7-methylthieno[3,2-d]pyrimidine

4-chloro-7-methylthieno[3,2-d]pyrimidine (800 mg, 4.33 mmol),2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.37 mL,6.5 mmol), Pd(dppf)Cl₂ (169 mg, 0.26 mmol), and K₃PO₄ (3679 mg, 17.33mmol) were weighed into a 40-mL vial. Then 1,4-dioxane (8 mL) and water(2 mL) was added. The mixture was purged with N₂ for 2 mins. Then it washeated overnight. The mixture was diluted with water and extracted byethyl acetate twice. The combined organic layer was dried over Na₂SO₄.The solution was concentrated to dryness and the residue was purified byauto flash column chromatography system on a pre-packed silica gelcolumn (40 g) using EtOAc/heptanes (5-70%) to give the title compound(840 mg, 3.88 mmol, 89.6% yield) as a white solid. LC-MS calc. forC₁₂H₁₃N₂S [M+H]⁺: m/z=217.08; Found 217.04.

Step 2: 4-Cyclopentyl-7-methylthieno[3,2-d]pyrimidine

To a suspension of 4-(cyclopenten-1-yl)-7-methylthieno[3,2-d]pyrimidine(800.0 mg, 3.7 mmol) and Pd/C (5 wt % Pd, 100.0 mg, 0.94 mmol) inmethanol (20 mL), 3 drops of AcOH was added. The mixture was stirredovernight under a H₂ atmosphere. The solvent was removed under vacuum.The residue was purified by flash chromatography on a silica gel column(0-30% EtOAc/heptane with 0.1% Et₃N) to afford the title compound (720mg, 3.30 mmol, 89.2% yield) as a white solid. LC-MS calc. for C₁₂H₁₅N₂S[M+H]⁺: m/z=219.10; Found 219.08.

Step 3:4-(4-Cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. ¹H NMR (300 MHz, methanol-d₄) δ9.50-9.05 (m, 1H), 9.04-8.91 (m, 1H), 8.46-8.30 (m, 2H), 7.68-7.55 (m,1H), 3.67 (d, J=12.1 Hz, 2H), 3.35 (s, 3H), 3.22 (d, J=12.9 Hz, 2H),2.94 (s, 3H), 2.75 (dd, J=14.4, 3.1 Hz, 2H), 2.44-1.78 (m, 12H). LC-MScalc. for C₂₇H₃₀FN₇S [M+H]⁺: m/z=504.23; Found 504.03.

Example 50.N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxido-7-propan-2-ylthieno[3,2-b]pyridin-4-ium-2-yl)pyrimidin-2-amine

Step 1:2-(2-Chloro-5-fluoropyrimidin-4-yl)-4-oxido-7-propan-2-ylthieno[3,2-b]pyridin-4-ium

A mixture of2-(2-chloro-5-fluoropyrimidin-4-yl)-7-propan-2-ylthieno[3,2-b]pyridine(20.0 mg, 0.06 mmol) and mCPBA (16.82 mg, 0.10 mmol) in DCM (3 mL) wasstirred at r.t. for 1 h. The reaction was quenched with H₂O (2 mL) andextracted with DCM (2 mL×3). The combined organic layers wereconcentrated and purified by prep-HPLC on C₁₈ column using mobile phase20% to 100% MeCN/H₂O (t_(R)=15 min) to afford the title compound (9.1mg, 43%) as a bright yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.72 (d,J=1.7 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.32 (d, J=6.5 Hz, 1H), 7.20 (d,J=6.5 Hz, 1H), 3.33-3.17 (m, 1H), 1.45 (d, J=6.9 Hz, 6H).

Step 2:N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxido-7-propan-2-ylthieno[3,2-b]pyridin-4-ium-2-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Step 5. ¹H NMR (300 MHz, CD₃OD) δ 8.85 (d, J=3.0Hz, 1H), 8.61 (d, J=0.9 Hz, 1H), 8.48 (d, J=6.5 Hz, 1H), 8.24 (dd,J=9.6, 2.9 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.59 (d, J=9.6 Hz, 1H), 7.53(d, J=6.5 Hz, 1H), 4.05-3.86 (m, 2H), 3.85-3.64 (m, 2H), 3.40-3.24 (m,7H), 1.49 (d, J=6.9 Hz, 6H), 1.43 (t, J=7.3 Hz, 3H). LC-MS calc. forC₂₅H₂₉FN₇OS [M+H]⁺: m/z=494.2/495.2; Found 494.1/495.3.

Example 51.2-[5-Fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one

Step 1: 1-(5-Bromo-4-methylthiophen-2-yl)-2-methylpropan-1-one

To a suspension of aluminum chloride (1.66 g, 12.43 mmol) in DCM (20 mL)at 0° C. was added isobutyryl chloride (1.32 g, 12.43 mmol) dropwise,next 2-bromo-3-methylthiophene (2.0 g, 11.3 mmol) was added slowly at 0°C. The resulting mixture was stirred at rt overnight. The reaction wasquenched with water (20 mL) and extracted with DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column using EtOAc/heptanes (0-10%) toafford the title compound (2.11 g, 75.2%). ¹H NMR (300 MHz, CDCl₃) δ7.39 (s, 1H), 3.35-3.19 (m, 1H), 2.22 (s, 3H), 1.21 (d, J=6.9 Hz, 6H).

Step 2: Ethyl(E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoate

To a suspension of sodium hydride (407.8 mg, 10.2 mmol) in THE (20 mL)at 0° C. was added triethyl phosphonoacetate (2.11 g, 9.4 mmol) dropwiseat 0° C. The reaction mixture was stirred at 0° C. for 30 min and thenstirred at rt for 30 min. A solution of1-(5-bromo-4-methylthiophen-2-yl)-2-methylpropan-1-one (2.1 g, 8.5 mmol)in THE (5 mL) was added dropwise. The reaction mixture was stirred at rtfor 2 days. The reaction was quenched with water (20 mL) and extractedwith EtOAc (20 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield thetitle compound (2.01 g), which was used for the next reaction withoutfurther purification.

Step 3: (E)-3-(5-Bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic Acid

To a solution of ethyl(E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoate (2.01 g, 6.3mmol) in methanol (10 mL) was added a solution of sodium hydroxide (1.26g, 31.52 mmol) in water (10 mL) dropwise. The reaction mixture wasstirred at 65° C. for 1 h. The solvent was removed under reducedpressure. The residue was dissolved in EtOAc (20 mL) and acidify with 2NHCl solution (20 mL). The layer was separated, and the aqueous layer wasextracted with EtOAc (20 mL×3). The combined organic layers were washedwith brine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield the title compound (1.30 g), which was usedfor the next reaction without further purification.

Step 4: 2-Bromo-3-methyl-7-propan-2-yl-5H-thieno[3,2-c]pyridin-4-one

To a solution of(E)-3-(5-bromo-4-methylthiophen-2-yl)-4-methylpent-2-enoic acid (1.30 g,4.50 mmol) and triethyamine (1.93 g, 13.49 mmol) in diphenyl ether (10mL) was added diphenyl phosphoryl azide (1.86 g, 6.74 mmol) dropwise.The reaction mixture was stirred at rt for 30 min and heated at 180° C.for 30 min. The reaction was quenched with 1 N NaOH solution (10 mL) andstirred at rt for 30 min. The reaction was extracted with EtOAc (20mL×3). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on a silica gel columnusing EtOAc/heptanes (5-90%) to afford the title compound (0.45 g,35.0%). ¹H NMR (300 MHz, CDCl₃) δ 10.75 (s, 1H), 6.95 (s, 1H), 3.00-2.76(m, 1H), 2.64 (s, 3H), 1.31 (d, J=6.9 Hz, 6H).

Step 5: 2-Bromo-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one

To a solution of2-bromo-3-methyl-7-propan-2-yl-5H-thieno[3,2-c]pyridin-4-one (105.0 mg,0.37 mmol) in DMF (1 mL) was added cesium carbonate (239.1 mg, 0.73mmol), followed by the addition of iodomethane (104.2 mg, 0.73 mmol).The reaction mixture was stirred at rt for 1 h. The reaction wasquenched with water (2 mL) and extracted with EtOAc (2 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on a silica gel column using EtOAc/heptanes (5-70%) toafford the title compound (75.0 mg, 68.1% yield). ¹H NMR (300 MHz,CDCl₃) δ 7.03 (s, 1H), 3.71 (s, 3H), 3.00-2.78 (m, 1H), 2.60 (s, 3H),1.34 (d, J=6.9 Hz, 6H).

Step 6:2-(2-Chloro-5-fluoropyrimidin-4-yl)-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one

To a solution of2-bromo-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one (130.0 mg,0.43 mmol) and bis(pinacolato)diboron (164.9 mg, 0.65 mmol) in1,4-dioxane (3 mL) was added KOAc (127.5 mg, 1.3 mmol) and1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium (1:1) (31.7 mg,0.04 mmol). The reaction mixture was purged with N₂ for 5 min andstirred at 100° C. for 1 h. LCMS showed the starting material wasconsumed. The reaction was cooled to rt and a solution of K₃PO₄ (275.8mg, 1.3 mmol) in water (1 mL) was added. The resulting mixture wasstirred at rt for 30 min. Next 2,6-dichloro-5-fluororacil (108.4 mg,0.65 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.7 mg,0.04 mmol) was added. The reaction mixture was purged with N₂ for 5 minand stirred at 100° C. overnight. LCMS showed the starting material wasconsumed. The solvent was removed under reduced pressure. The residuewas purified by prep-HPLC on a C18 column eluting with MeCN/H₂O(20-100%) to yield the title compound (14.1 mg, 9.2% yield). LCMS calc.for C₁₆H₁₆ClFN₃OS [M+H]⁺: m/z=352.07/354.07; Found: 352.0/353.9.

Step 7:2-[5-Fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Step 5. ¹H NMR (300 MHz, CD₃OD) δ 8.77 (d, J=2.7Hz, 1H), 8.23 (dd, J=9.6, 3.0 Hz, 1H), 7.91 (d, J=2.9 Hz, 1H), 7.59 (d,J=9.6 Hz, 1H), 7.46 (s, 1H), 3.63 (s, 3H), 4.00-3.10 (m, 8H), 3.05-2.93(m, 4H), 2.85 (s, 3H), 1.40 (d, J=7.0 Hz, 6H). LCMS calc. forC₂₆H₃₁FN₇OS [M+H]⁺: m/z=508.2/509.2; Found: 508.2/509.4.

Example 52:4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1. Methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate

Sodium triacetoxyborohydride (13.5 g, 63.7 mmol) was added in portionsto a mixture of methyl 2-amino-4-methylthiophene-3-carboxylate (7.27 g,42.5 mmol), 2-methoxyprop-1-ene (4.6 g, 63.7 mmol), and acetic acid(3.64 mL, 63.7 mmol) in DCE (140 mL). The resulting mixture was stirredfor 4 h. The reaction mixture was slowly poured into 10% Na₂CO₃ (aq) andstirred until gas evolution ceased (30 min). The organic layer wasseparated, and the aqueous layer extracted with DCM (60 mL×3). Thecombined organic layers were washed with 10% Na₂CO₃ (aq) (60 mL), water(60 mL), and brine (60 mL); dried over Na₂SO₄; filtered; andconcentrated. The crude product was purified by silica gelchromatography (0-10% MTBE/heptanes) to give the title compound (7.81 g,36.6 mmol, 86.1% yield) as colorless oil. LCMS calc. for C₁₀H₁₆NO₂S[M+H]⁺: m/z=214.1; Found: 214.2.

Step 2. 2-(Isopropylamino)-4-methylthiophene-3-carboxylic Acid

A solution of NaOH (8.78 g, 220 mmol) in water (70 mL) was added to asolution of methyl 2-(isopropylamino)-4-methylthiophene-3-carboxylate(7.81 g, 36.6 mmol) in methanol (70 mL). The reaction mixture was heatedat 70° C. for 18 h. The organic solvent was removed under reducedpressure. The remaining aqueous mixture was diluted with water (20 mL),acidified to pH 3 with 2 N HCl, and extracted with MTBE (30 mL×3). Thecombined organic layers were washed with water (30 mL) and brine (30mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to affordthe title compound (6.26 g, 31.4 mmol, 85.8% yield) as an amber solid,which was used in the next step without further purification. LCMS calc.for C₉H₁₄NO₂S [M+H]⁺: m/z=200.1; Found: 200.1.

Step 3. 2-(N-Isopropylacetamido)-4-methylthiophene-3-carboxylic Acid

Acetic anhydride (7.43 mL, 78.6 mmol) was added dropwise to a mixture of2-(isopropylamino)-4-methylthiophene-3-carboxylic acid (6.26 g, 31.4mmol), triethylamine (13.1 mL, 94.3 mmol) and 4-(dimethylamino)pyridine(0.38 g, 3.14 mmol) in DCM (60 mL) at room temperature. The resultinglight amber solution was stirred for 18 h. The reaction mixture waspoured into water (80 mL) and extracted with DCM (30 mL×3). The combinedorganic layers were washed sequentially with water (30 mL) and brine (30mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (0-50% EtOAc/heptanes) to give thetitle compound (4.71 g, 19.5 mmol, 62.1% yield) as yellow viscous oil.LCMS calc. for C₁₁H₁₆NO₃S [M+H]⁺: m/z=242.1; Found: 242.1.

Step 4. N-(3-Amino-4-methylthiophen-2-yl)-N-isopropylacetamide

To mixture of 2-(N-isopropylacetamido)-4-methylthiophene-3-carboxylicacid (4.71 g, 19.5 mmol) and triethylamine (8.15 mL, 58.5 mmol) in1,4-dioxane (25 mL), was added diphenyl phosphoryl azide (8.05 g, 29.2mmol) dropwise over 30 min. The resulting mixture was stirred for 1 h.Water (25 mL) was added, and the reaction mixture was heated at 100° C.for 18 h. After cooling to room temperature, 2 N NaOH (aq) (10 mL) wasadded. The resulting mixture was stirred for 15 min and then extractedwith DCM (50 mL×3). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered, and concentrated to afford thetitle compound, which was used in the subsequent step without furtherpurification. LCMS calc. for C₁₀H₁₇N₂OS [M+H]⁺: m/z=213.1; Found: 213.1.

Step 5. 3-Isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole

To the solution of crudeN-(3-amino-4-methylthiophen-2-yl)-N-isopropylacetamide (from Step 4) intoluene (40 mL) was added POCl₃ (3.29 mg, 21.5 mmol) slowly at roomtemperature, and then the mixture was heated at 100° C. for 18 h. Thereaction mixture was poured onto ice-cold 10% Na₂CO₃ (aq) with vigorousstirring. The organic layer was separated, and the aqueous layer wasextracted with EtOAc (40 mL×3). The combined organic layers were washedwith 10% Na₂CO₃ (aq) (40 mL) and brine (40 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (0-75% EtOAc/heptanes with 0.1% NEt₃) to give the titlecompound (2.88 g, 14.8 mmol, 75.9% yield over two steps) as a red oil.LCMS calc. for C₁₀H₁₅N₂S [M+H]⁺: m/z=195.1; Found: 195.1.

Step 6.3-Isopropyl-2,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-thieno[2,3-d]imidazole

A solution of lithium diisopropylamide (5.43 mL, 41.0 mmol) (2.0 M inTHF/ethylbenzene/hexanes) was added dropwise to a mixture of3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole (1.60 g, 8.21 mmol)and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.19 mL, 20.5mmol) in THE (50 mL) at −78° C. The mixture was stirred at −78° C. After4 h, the reaction was quenched by the dropwise addition of sat. NH₄Cl(aq) (75 mL) at 0° C. The mixture was extracted with EtOAc (75 mL×3) and1:1 CHCl₃/iPrOH (75 mL×3). The combined organic layers were dried oversodium sulfate, filtered, and concentrated to afford the title compound,which was used in the next step without further purification. LCMS calc.for C₁₆H₂₆BN₂O₂S [M+H]⁺: m/z=321.2; Found: 321.1.

Step 7.5-(2-Chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole

A suspension of 2,6-dichloro-5-fluororacil (1.77 g, 10.6 mmol),3-isopropyl-2,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-thieno[2,3-d]imidazole(from Step 6),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (323 mg,0.44 mmol), and K₃PO₄ (7.50 g, 35.4 mmol) in 1,4-dioxane (16 mL) andwater (4 mL) was heated at 100° C. under a nitrogen atmosphere for 18 h.The reaction mixture was cooled to room temperature and partitionedbetween EtOAc (20 mL) and water (20 mL). The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (15 mL×3). Thecombined organic layers were washed with water (15 mL) and brine (15mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (0-75% EtOAc/heptanes containing0.1% NEt₃) and then repurified via prep-HPLC on a C18 column (15-60%MeCN/H₂O containing 0.1% TFA) to afford the title compound as its TFAsalt (1.57 g, 3.58 mmol, 43.7% yield for two steps) as yellow solid.LCMS calc. for C₁₄H₁₅ClFN₄S [M+H]⁺: m/z=325.1; Found: 325.0.

Step 8.4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

A suspension of5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole,TFA salt (500 mg, 1.14 mmol), XPhos Pd G2 (121 mg, 0.15 mmol), K₃PO₄(980 mg, 4.62 mmol) and5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-amine (437 mg, 2.0mmol) in 1,4-dioxane (10 mL) and DMSO (1 mL) was heated at 100° C. undera nitrogen atmosphere for 5 h. The reaction mixture was cooled to roomtemperature, diluted with MeOH (5 mL), filtered, and purified byprep-HPLC on C18 column (5-40% MeCN/H₂O containing 0.1% TFA) to affordtitle compound as its TFA salt (701 mg, 0.955 mmol, 62.0% yield). ¹H NMR(300 MHz, methanol-d₄) δ 8.47 (d, J=3.5 Hz, 1H), 7.95 (d, J=9.0 Hz, 1H),7.58 (d, J=2.8 Hz, 1H), 7.22 (dd, J=9.1, 2.9 Hz, 1H), 4.81-4.76 (m, 1H),4.41 (s, 4H), 4.16 (s, 4H), 3.30 (q, J=7.3 Hz, 2H), 2.65 (s, 3H), 2.64(s, 3H), 1.62 (d, J=6.7 Hz, 6H), 1.26 (t, J=7.2 Hz, 3H). LC-MS calc. forC₂₆H₃₂FN₈S [M+H]⁺: m/z=507.2; Found 506.9.

Example 53:6-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine

Step 1.5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

To a suspension of5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazole(138 mg, 0.426 mmol) in 2-propanol (2 mL) was added aqueous solution ofNH₄OH (2.0 mL, 0.42 mmol, 33%). The resulting mixture was stirred at100° C. in a sealed tube for 2 d. After cooling to room temperature, thevolatiles were removed in vacuo. The residue was purified by prep-HPLCon a C18 column (15-60% MeCN/H₂O containing 0.1% TFA) to afford thetitle compound as its TFA salt (122 mg, 0.291 mmol, 68.4% yield) asyellow solid. LCMS calc. for C₁₄H₁₇FN₅S [M+H]⁺: m/z=306.1; Found: 305.9.

Step 2. Tert-Butyl6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a solution of 3,6-dichloropyridazine (500 mg, 3.36 mmol) in1,4-dioxane (10 mL) was added tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (665 mg, 3.36 mmol), K₃PO₄(2.14 g, 10.1 mmol), and XPhos Pd G2 (264 mg, 0.34 mmol). The mixturewas stirred at 100° C. under a N₂ atmosphere for 24 h. After cooling toroom temperature, water was added (10 mL), and the mixture was extractedwith EtOAc (10 mL×3). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (10-90% EtOAc/heptanes) toafford the title compound (545 mg, 1.75 mmol, 52.1% yield). LCMS calc.for C₁₄H₂₀ClN₄O₂[M+H]⁺: m/z=311.1, 313.1; Found 311.1, 313.0.

Step 3. 2-(6-Chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane

To a solution of tert-butyl6-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (545mg, 1.75 mmol) in DCM (5 mL) was added TFA (5.0 mL, 65 mmol). Themixture was stirred for 3 h and then concentrated under reduced pressureto provide the title compound (350 mg, 1.66 mmol, 94.9% yield). LCMScalc. for C₉H₁₂ClN₄ [M+H]⁺: m/z=211.0; Found 211.1.

Step 4. 2-(6-Chloropyridazin-3-yl)-6-ethyl-2,6-diazaspiro[3.3]heptane

To a solution of 2-(6-chloropyridazin-3-yl)-2,6-diazaspiro[3.3]heptane(350 mg, 1.66 mmol) in MeOH (4 mL) was added triethylamine (0.46 mL,3.32 mmol), acetaldehyde (365 mg, 8.31 mmol), acetic acid (100 mg, 1.66mmol), and sodium cyanoborohydride (1.04 g, 16.6 mmol). The mixture wasstirred at room temperature overnight. Water (10 mL) was added, and theresulting mixture was extracted with ethyl acetate (5 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the title compound (300mg, 1.26 mmol, 75.9% yield). LCMS calc. for C₁₁H₁₆ClN₄ [M+H]+:m/z=239.1; Found 239.2.

Step 5.6-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine

A suspension of5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine(53 mg, 0.17 mmol),2-(6-chloropyridazin-3-yl)-6-ethyl-2,6-diazaspiro[3.3]heptane (38 mg,0.16 mmol), sodium tert-butoxide (61 mg, 0.63 mmol), and BrettPhos Pd G3(7.2 mg, 0.010 mmol, CAS: 1470372-59-8) in 1,4-dioxane (1 mL) was heatedat 100° C. for 18 h. The reaction mixture was cooled to room temperatureand diluted with MeOH (2 mL). The solid salts were removed byfiltration, and the filtrate was purified by prep-HPLC on C-18 column(6-80% MeCN/H₂O containing 0.1% TFA) to afford the title compound as aTFA salt (25 mg, 0.034 mmol, 21% yield) as yellow solid. ¹H NMR (300MHz, CD₃OD) δ 8.71 (d, J=3.0 Hz, 1H), 8.13 (d, J=9.8 Hz, 1H), 7.53 (d,J=9.9 Hz, 1H), 5.03-4.97 (m, 1H), 4.55-4.29 (m, 8H), 3.28-3.23 (m, 2H),2.83 (s, 3H), 2.69 (d, J=3.1 Hz, 3H), 1.66 (d, J=6.6 Hz, 6H), 1.22 (t,J=7.2 Hz, 3H). LCMS calc. for C₂₅H₃₁FN₉S [M+H]⁺: m/z=508.2; Found 508.0.

Example 54:(4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone

Step 1. (6-Aminopyridin-3-yl)(4-ethylpiperazin-1-yl)methanone

To a solution of 6-aminonicotinic acid (200 mg, 1.45 mmol) in1,4-dioxane (10 mL) was added thionyl chloride (0.1 mL, 1 mmol). Uponstirring at room temperature for 3 h, 1-ethylpiperazine (0.19 mL, 1.5mmol) was added. The mixture was stirred for an additional 24 h. Water(10 mL) and solid NaHCO₃ were added to adjust to pH>8. The solvent wasremoved under reduced pressure. The residue was purified by prep-HPLC onC₁₈ column (10-100% MeCN/H₂O) to afford the title compound (149 mg,0.637 mmol, 43.9% yield). LCMS calc. for C₁₂H₁₉N₄O [M+H]⁺: m/z=235.3;Found 235.2.

Step 2.(4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone

The TFA salt of the title compound is synthesized by proceduresanalogous to those outlined in Example 1, Step 8. ¹H NMR (300 MHz,methanol-d₄) δ 8.69 (d, J=3.1 Hz, 1H), 8.53-8.49 (m, 1H), 8.19 (d, J=8.9Hz, 1H), 8.12 (dd, J=8.9, 2.2 Hz, 1H), 8.09 (d, J=0.9 Hz, 1H), 5.10-4.91(m, 1H), 3.88-3.34 (m, 6H), 3.30-3.15 (m, 4H), 2.87 (s, 3H), 1.71 (d,J=6.7 Hz, 6H), 1.40 (t, J=7.3 Hz, 3H). LCMS calc. for C₂₅H₃₀FN₈OS[M+H]⁺: m/z=509.2; Found 509.0.

Example 55:4-(2,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1: 2,4-Dimethylthiophen-3-amine

A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (30.0 g,175 mmol) in dioxane (20 mL) was added over 10 min to a stirred solutionof lithium aluminum hydride (13.3 g, 350 mmol) in 1,4-dioxane (250 mL)at 80° C. The resulting mixture was stirred at 100° C. for 30 min. Thereaction mixture was cooled to room temperature and diluted with MTBE(300 mL). The reaction was quenched by sequential addition of water (60mL), 15% NaOH (aq) (60 mL), and water (180 mL). After stirring for 30min, the reaction mixture was extracted with EtOAc (200 mL×2), and thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated to afford the title compound (23.0 g, 181mmol) as an orange oil. This material was used in next step withoutfurther purification. LC-MS: [M+H]⁺ calc. for C₆H₁₀NS: 128.1; Found:128.0.

Step 2. 1-(6-Methylthieno[3,2-c]pyrazol-1-yl)ethanone

To a solution of 2,4-dimethylthiophen-3-amine (23.0 g, 181 mmol) intoluene (250 mL) was added KOAc (17.74 g, 180.8 mmol) and dropwiseacetic anhydride (34.18 mL, 361.6 mmol). Upon heating to 80° C., isoamylnitrite (36.15 mL, 271.2 mmol) was added dropwise over 10 min. Themixture was then heated at 95° C. for 1 h. The reaction was quenched byaddition of saturated NaHCO₃ (aq) (50 mL). The reaction mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were driedover sodium sulfate, filtered, and concentrated. The crude product waspurified by silica gel chromatography (5-30% EtOAc/heptane) to affordthe title compound (31.9 g, 177 mmol, 97.8% yield) as an orange solid.LCMS (C18 column; 0.8 mL/min; MeCN/H₂O with 0.1% formic acid; 5% 1 min,5-95% 4 min, 95% 2 min) t_(R)=3.57 min. LCMS calc. forC₆H₇N₂S[M+H-COCH₃]⁺: m/z=139.0; Found: 138.9.

Step 3. 6-Methyl-1H-thieno[3,2-c]pyrazole

To a solution of 1-(6-methylthieno[3,2-c]pyrazol-1-yl)ethanone (31 g,0.17 mol) in ethanol (120 mL) and water (120 mL) was added conc. HCl(143 mL, 1.72 mol). The resulting mixture was stirred at 60° C. for 2 h.The reaction mixture was diluted with water (50 mL), and the reactionquenched with NaHCO₃ to reach pH 8-9. The reaction mixture was extractedwith DCM (50 mL×3). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated. The crude product was purified bysilica gel chromatography (3-30% EtOAc/heptanes) to afford the titlecompound (23 g, 0.16 mol, 95% yield) as a sticky brown solid. LCMS (C18column; 0.8 mL/min; MeCN/H₂O with 0.1% formic acid; 5% 1 min, 5-95% 4min, 95% 2 min) t_(R)=3.32 min. LCMS calc. for C₆H₇N₂S [M+H]⁺:m/z=139.0; Found: 138.9.

Step 4. 3-Iodo-6-methyl-1H-thieno[3,2-c]pyrazole

To a solution of 6-methyl-1H-thieno[3,2-c]pyrazole (22 g, 160 mmol) inmethanol (200 mL) was added K₂CO₃ (48.4 g, 350 mmol) and iodine (44.5 g,175 mmol). The resulting mixture was stirred at room temperatureovernight. The reaction was quenched by the addition 10% Na₂S₂O₃ (aq)(50 mL), and the reaction mixture was extracted with EtOAc (50 mL×2).The combined organic layers were dried over sodium sulfate, filtered,and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography (0-30% EtOAc/heptanes) to afford the titlecompound (37 g, 140 mmol, 88% yield) as a red solid. LCMS calc. forC₆H₆IN₂S [M+H]⁺: m/z=264.9; Found: 264.8.

Step 5. 3-Iodo-2,6-dimethylthieno[3,2-c]pyrazole

A suspension of 3-iodo-6-methyl-1H-thieno[3,2-c]pyrazole (30 g, 114mmol) and NaHCO₃ (19.1 g, 227 mmol) in DCM (400 mL) was added to a vialcharged with trimethyloxonium tetrafluoroborate (17.6 g, 119 mmol).After stirring at room temperature for 1 h, the reaction was quenchedwith water (200 mL). The reaction mixture was extracted with EtOAc (200mL×3), and the combined organic phase was dried over Na₂SO₄, filtered,and. The residue was purified by silica gel chromatography (5-50%EtOAc/heptanes) to afford the title compound (29 g, 100 mmol, 92%yield). LCMS calc. for C₇H₈IN₂S [M+H]⁺: m/z=278.9; Found: 278.8.

Step 6: 2,6-Dimethyl-3-prop-1-en-2-ylthieno[3,2-c]pyrazole

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Step 1. LCMS calc. for C₁₀H₁₃N₂S [M+H]⁺:m/z=193.1; Found: 193.0.

Step 7. 2,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazole

To a stirred solution of2,6-dimethyl-3-prop-1-en-2-ylthieno[3,2-c]pyrazole (14 g, 73 mmol) inacetic acid (100 mL) was added 5% Pd/C (0.77 g, 7.3 mmol). The reactionvessel was charged with H₂, and the reaction mixture was stirred in aParr shaker for 3 d. The reaction mixture was filtered through a pad ofCelite, and the filtrate was concentrated. The residue was purified bysilica gel chromatography (5-30% EtOAc/heptanes) to afford the titlecompound (11.8 g, 60.7 mmol, 83.1% yield). LCMS calc. for C₁₀H₁₅N₂S[M+H]⁺: m/z=195.1; found 195.0.

Step 8.2,6-Dimethyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyrazole

The title compound is synthesized by procedures analogous to thoseoutlined in Example 52, Step 6. LCMS calc. for C₁₆H₂₆BN₂O₂S [M+H]⁺:m/z=321.2; Observed: 321.0.

Step 9.5-(2-Chloro-5-fluoropyrimidin-4-yl)-2,6-dimethyl-3-propan-2-ylthieno[3,2-c]pyrazole

The title compound is synthesized by procedures analogous to thoseoutlined in Example 52, Step 7. LCMS calc. for C₁₄H₁₅ClFN₄S [M+H]⁺:m/z=325.1, 327.1; Found: 324.8, 326.8.

Step 10.4-(2,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 1, Step 8. Purification via silica gelchromatography (1-10% MeOH/DCM) and recrystallizion in EtOAc affordedthe title compound as a light yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ9.70 (s, 1H), 8.62 (d, J=2.8 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.59 (d,J=2.9 Hz, 1H), 6.95 (dd, J=8.9, 3.0 Hz, 1H), 4.00 (s, 3H), 3.95 (s, 4H),3.91 (s, 4H), 3.40-3.25 (m, 1H), 2.87 (q, J=7.2 Hz, 2H), 2.40 (d, J=3.4Hz, 3H), 1.32 (d, J=6.8 Hz, 6H), 0.99 (t, J=7.1 Hz, 3H). LCMS calc. forC₂₆H₃₂FN₈S [M+H]⁺: m/z=507.2; Found 507.0.

Example 56:2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

Step 1. tert-Butyl6-nitro-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (12.0 g,38.8 mmol), 5-bromo-2-nitropyridine (7.80 g, 38.4 mmol), sodiumcarbonate (15.9 g, 115 mmol), and1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.51 g, 3.84mmol) were suspended in 1,4-dioxane (120 mL) and water (40.0 mL) underinert atmosphere. The reaction mixture was heated at 100° C. for 6 h.The reaction mixture was cooled to room temperature and diluted withwater (100 mL). The mixture was extracted with EtOAc (100 mL×3). Theorganic layers were combined, washed with brine, dried over sodiumsulfate, filtered, and concentrated. The crude residue was purified bysilica gel chromatography using EtOAc in heptanes (10-60% with 0.1%Et₃N) to afford the title compound (9.20 g, 30.1 mmol, 78.4% yield) as abrown solid. LCMS calc. for C₁₅H₂₀N₃O₄ [M+H]⁺: m/z=306.1; Found: 306.1.

Step 2. 6-Nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine

tert-Butyl 6-nitro-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate(11.0 g, 36.0 mmol) was dissolved in DCM (30.0 mL) and cooled to 0° C.Trifluoroacetic acid (10.0 mL, 131 mmol) was added slowly at 0° C. Thereaction mixture was warmed to room temperature and stirred for 5 h. Thereaction mixture was concentrated under reduced pressure and thendiluted with water (10.0 mL). The solution was lyophilized and usedwithout further purification to afford the crude TFA salt of the titlecompound (18.6 g) as a yellow solid. LCMS calc. for C₁₀H₁₂N₃O₂ [M+H]⁺:m/z=206.1; Found: 206.0.

Step 3. 1′-Methyl-6-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine

Formaldehyde (24.9 mL, 335 mmol, 37 wt % in H₂O) and the crude TFA saltof 6-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (18.6 g) weredissolved in DCM (60 mL) at room temperature. The mixture was stirredfor 30 min, and the reaction was cooled to 0° C. Sodiumtriacetoxyborohydride (14.2 g, 66.9 mmol) was added portion-wise at 0°C. The resulting reaction mixture was allowed to warm to roomtemperature and stirred overnight. The reaction was quenched with sat.sodium bicarbonate (aq) (60.0 mL), and sodium carbonate was added untilgas evolution was no longer observed. The organic phase was separated,and the aqueous layer was extracted with DCM (30.0 mL×2). The organiclayers were combined, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The reaction sequence in steps 2-3was repeated with an additional portion of tert-butyl6-nitro-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (2.5 mmol inStep 2), and the crude material from both sequences was combined forpurification. Purification by silica gel chromatography using MeOH inDCM (0-50%) afforded the freebase of the title compound (8.10 g, 36.9mmol, quantitative yield over two steps) as a yellow solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.74 (d, J=2.1 Hz, 1H), 8.29-8.16 (m, 2H), 6.57 (t,J=3.6 Hz, 1H), 3.09-3.03 (m, 2H), 2.60-2.52 (m, 4H), 2.27 (s, 3H). LCMScalc. for C₁₁H₁₄N₃O₂ [M+H]⁺: m/z=220.1; Found: 220.0.

The freebase was dissolved in EtOAc (50.0 mL), DCM (5.00 mL), and MeOH(5.00 mL). Then a solution of HCl (37.0 mL, 74.0 mmol, 2N in iPrOAc) wasadded. The reaction mixture was stirred for 2 h at room temperature. Theprecipitate was collected by filtration and dried under reduced pressureto afford the HCl salt of the title compound (9.46 g, 32.4 mmol, 90.1%yield) as a white solid.

Step 4. 5-(1-Methylpiperidin-4-yl)pyridin-2-amine

In a 500 mL reaction vessel,1′-methyl-6-nitro-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine, HCl salt (9.46g, 32.4 mmol) was dissolved in MeOH (150 mL). Palladium on carbon (0.875g, 0.822 mmol, 10 wt %) and glacial acetic acid (1.00 mL, 17.5 mmol)were added sequentially at room temperature. The reaction vessel wassealed in a Parr shaker, and the vessel was charged with hydrogen (60psi). The reaction mixture was mixed overnight. The atmosphere ofhydrogen was removed, the mixture was filtered, and the filtrate wasconcentrated under reduced pressure. The dark residue was dissolved inDCM (30.0 mL) and neutralized with sodium hydroxide (3.39 g, 84.8 mmol).The organic layer was washed with water (30.0 mL×2), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The cruderesidue was purified by silica gel chromatography using MeOH in DCM(0-50% with 0.1% Et₃N) to afford the title compound (6.10 g, 31.9 mmol,98.5% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (d,J=2.2 Hz, 1H), 7.23 (dd, J=8.5, 2.4 Hz, 1H), 6.36 (d, J=8.5 Hz, 1H),5.62 (s, 2H), 2.81 (d, J=11.4 Hz, 2H), 2.40-2.16 (m, 1H), 2.15 (s, 3H),2.00-1.75 (m, 2H), 1.64-1.47 (m, 4H). LCMS calc. for C₁₁H₁₈N₃[M+H]⁺:m/z=192.1; Found: 192.1.

Step 5.2-(2-Chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

Butyllithium (5.20 mL, 13.0 mmol, 2.5 M in hexanes) was added dropwiseto a solution of2-bromo-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one (2.60 g,8.66 mmol, Example 51, Step 5) at −78° C. The reaction mixture wasstirred for 20 min at −78° C. 2-Chloro-5-fluoropyrimidine (1.38 g, 10.4mmol) was then added in a single portion. The reaction mixture stirredfor 30 min at −78° C. The reaction was quenched with sat. NH₄Cl (aq) anddiluted with DCM (30.0 mL). The mixture was allowed to warm to roomtemperature, and the two phases were separated. The organic layer wasremoved, and the aqueous layer was extracted with DCM (30.0 mL×2). Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated.

To the crude residue in THE (30.0 mL) was added2,3-dichloro-5,6-dicyano-p-benzoquinone (1.86 g, 8.20 mmol). Thereaction mixture stirred for 30 min at room temperature. The reactionmixture was diluted with DCM (30.0 mL), washed with hot potassiumcarbonate (10 wt % aq.) (30.0 mL×2), dried over sodium sulfate, andconcentrated. The crude residue was purified by prep-HPLC using a C18column (20-100% MeCN/0.1% TFA (aq.)) to afford the title compound as theTFA salt (1.35 g, 2.90 mmol, 35.3% yield), an off-white solid. LCMScalc. for C₁₆H₁₆ClFN₃OS [M+H]⁺: m/z=352.1, 354.1; Found: 352.0, 353.9.

Step 6.2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

To a solution of2-(2-chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one,TFA salt (1.20 g, 2.58 mmol) and5-(1-methylpiperidin-4-yl)pyridin-2-amine (0.783 g, 4.09 mmol) in1,4-dioxane (24.0 mL) was added K₃PO₄ (2.17 g, 10.2 mmol) and XPhos PdG2 (268 mg, 0.341 mmol, CAS 1310584-14-5). The reaction vessel wassealed, and the mixture was degassed with N₂ (3×). The reaction mixturewas heated at 100° C. overnight. The reaction mixture was cooled to roomtemperature, filtered, and concentrated under reduced pressure. The darkresidue was purified by prep-HPLC on a C18 column (10-50% MeCN/0.1% TFA(aq.)) to afford the title compound as the TFA salt. The TFA salt wasneutralized with sat. NaHCO₃ (aq) (20.0 mL), and the aqueous layer wasextracted with DCM (20.0 mL×3). The organic layers were combined, washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was dissolved in 1N HCl (2.20 mL, 2.20mmol, 1.05 equiv), and the solvent was removed by lyophilization toafford the HCl salt of the title compound (1.21 g, 2.23 mmol, 86.5%yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.46 (br s, 1H),10.31 (br s, 1H), 8.75 (d, J=2.5 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.12(d, J=8.7 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.55 (s, 1H), 3.52 (s,3H), 3.46 (s, 2H), 3.20-2.97 (m, 2H), 2.95-2.84 (m, 2H), 2.77 (d, J=4.3Hz, 3H), 2.69 (d, J=3.5 Hz, 3H), 2.06-1.93 (m, 4H), 1.31 (d, J=6.8 Hz,6H). LCMS calc. for C₂₇H₃₂FN₆OS [M+H]⁺: m/z=507.2; Found: 507.2.

Examples 57-61

Examples listed in Table 4-1 are synthesized according to proceduresanalogous to Example 51 and Example 56.

TABLE 4-1 Examples 57-61. Exam- LCMS ple R¹ R² R³ [M + H]⁺ 57 Me Me

534.1 58 Me H

519.9 59 Me H

536.3 60 H Me

493.0 61 Me Me

533.9

TABLE 4-2 Examples 57-61. Example Compound name NMR 572-(2-((5-(6-Ethyl-2,6- ¹H NMR (300 MHz, CD₃OD) δ 8.74diazaspiro[3.3]heptan-2- (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.5, 2.8yl)pyridin-2-yl)amino)-5- Hz, 1H), 7.55-7.35 (m, 3H), 4.51fluoropyrimidin-4-yl)-7- (d, J = 11.4 Hz, 2H), 4.40-4.22 isopropyl-3,5-(m, 4H), 4.18 (s, 2H), 3.63 (s, 3H), 3.26 dimethylthieno[3,2- (q, J =7.3 Hz, 2H), 3.00 (p, J = 6.0 Hz, c]pyridin-4(5H)- 1H), 2.84 (d, J = 3.3Hz, 3H), 1.39 one, TFA salt (d, J = 6.9 Hz, 6H), 1.23 (t, J = 7.2 Hz,3H). 58 2-(2-((5-(6-Ethyl-3,6- ¹H NMR (300 MHz, CD₃OD) δ 8.75diazabicyclo[3.1.1]heptan- (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.073-yl)pyridin-2-yl)amino)-5- (d, J = 9.5 Hz, 1H), 7.83 (s, 1H), 7.65fluoropyrimidin-4-yl)-7- (d, J = 9.6 Hz, 1H), 7.55 (s, 1H), 4.75isopropyl-5-methylthieno[3,2- (d, J = 6.0 Hz, 1H), 4.61 (d, J = 6.2 Hz,c]pyridin-4(5H)-one, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.10- TFA salt 3.75(m, 3H), 3.70 (s, 3H), 3.68-3.55 (m, 1H), 3.14-3.07 (m, 2H), 2.22 (dd, J= 15.7, 7.8 Hz, 2H), 1.46 (d, J = 6.9 Hz, 6H), 1.42-1.37 (m, 3H). 592-(2-((5-(4-Ethylpiperazine- ¹H NMR (300 MHz, DMSO-d₆) δ 10.561-carbonyl)pyridin-2- (s, 1H), 9.83 (s, 1H), 8.78 (d, J = 3.1 Hz,yl)amino)-5-fluoro- 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.29pyrimidin-4-yl)-7-isopropyl- (d, J = 8.8 Hz, 1H), 8.21 (d, J = 1.7 Hz,5-methylthieno[3,2- 1H), 7.96 (dd, J = 8.7, 2.4 Hz, 1H), 7.60c]pyridin-4(5H)-one, TFA salt (s, 1H), 3.54 (s, 3H), 3.52-3.02 (m, 10H),2.96 (p, J = 6.9 Hz, 1H), 1.34 (d, J = 6.8 Hz, 6H), 1.23 (t, J = 7.2 Hz,3H). 60 2-(5-Fluoro-2-((5-(1- ¹H NMR (300 MHz, CD₃OD) δ 8.80methylpiperidin-4- (d, J = 2.6 Hz, 1H), 8.31 (dd, J = 9.1, 2.3yl)pyridin-2-yl)amino)pyrimidin- Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.604-yl)-7- (d, J = 9.0 Hz, 1H), 7.18 (s, 1H), 3.68isopropyl-3-methylthieno[3,2- (d, J = 13.0 Hz, 2H), 3.27-2.95 (m,c]pyridin-4(5H)-one, 4H), 2.94 (s, 3H), 2.86 (d, J = 3.2, 3H), TFA salt2.23 (d, J = 14.2 Hz, 2H), 2.14-1.94 (m, 2H), 1.39 (d, J = 6.9 Hz, 6H).61 2-(5-Fluoro-2-((5-(6- ¹H NMR (400 MHz, DMSO-d₆) δ 10.72methyl-2,6-diazaspiro[3.4]octan- (s, 1H), 10.13 (s, 1H), 8.75 (d, J =2.6 2-yl)pyridin-2- Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.59yl)amino)pyrimidin-4-yl)-7- (d, J = 2.9 Hz, 1H), 7.56 (s, 1H), 7.34isopropyl-3,5-dimethylthieno[3,2- (dd, J = 9.1, 3.0 Hz, 1H), 3.99-3.89(m, c]pyridin-4(5H)-one, TFA salt 3H), 3.90-3.79 (m, 2H), 3.66-3.54 (m,1H), 3.51 (s, 3H), 3.29 (dd, J = 12.0, 7.2 Hz, 1H), 3.20-3.04 (m, 1H),2.90 (p, J = 6.8 Hz, 1H), 2.85 (d, J = 4.4 Hz, 3H), 2.70 (d, J = 3.4 Hz,3H), 2.44 (td, J = 8.5, 4.2 Hz, 1H), 2.26 (dt, J = 13.6, 8.4 Hz, 1H),1.31 (d, J = 6.8 Hz, 6H).

Example 62:6-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one

Step 1. 2-(Isopropylamino)-4-methylthiophene-3-carboxamide

Sodium triacetoxyborohydride (4.24 g, 20.0 mmol) was added portionwiseto a solution of 2-amino-4-methylthiophene-3-carboxamide (1.56 g, 10.0mmol), 2-methoxyprop-1-ene (1.92 mL, 20.0 mmol), and acetic acid (1.14mL, 20.0 mmol) in DCE (40.0 mL) at room temperature. The resultingsuspension was stirred for 3 h. Additional sodium triacetoxyborohydride(1.70 g, 8.00 mmol) was added portionwise to the reaction mixture. Thereaction suspension then stirred for 18 h. The reaction mixture wasslowly poured over 10% sodium carbonate (aq) (100 mL) and stirred untilgas evolution ceased. The organic layer was separated, and the aqueouslayer extracted with DCM (50 mL) and EtOAc (50 mL). The combined organiclayers were washed with water (50 mL) and brine (50 mL), dried oversodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography on silica gel using EtOAc in hexanes (20%) to givethe title compound (330 mg, 1.66 mmol, 16.6% yield) as an off-whitesolid. LCMS calc. for C₉H₁₅N₂OS [M+H]⁺: m/z=199.1; Found: 199.0.

Step 2. 1-Isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one

Formic acid (34.0 μL, 0.908 mmol) was added to a solution of2-(isopropylamino)-4-methylthiophene-3-carboxamide (180 mg, 0.908 mmol)in trimethyl orthoformate (1.00 mL) at room temperature. The reactionmixture was heated to 85° C. for 1 h. The reaction mixture was cooled toroom temperature and poured over 10% sodium bicarbonate (aq.). Theorganic layer was separated, and the aqueous layer extracted with EtOAc(20 mL×3). The combined organic layers were washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography on silica gel using MeOH in DCM (10%)to give the title compound (72.0 mg, 0.346 mmol, 38.1% yield) as anoff-white solid. LCMS calc. for C₁₀H₁₃N₂OS [M+H]⁺: m/z=209.1; Found:209.0.

Step 3. 6-Bromo-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one

N-Bromosuccinimide (26.2 mg, 0.149 mmol) was added to a mixture of1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one (31.0 mg, 0.149mmol) and indium(III) trifluoromethanesulfonate (8.4 mg, 0.015 mmol) inDCE (1.5 mL) at room temperature. The reaction mixture stirred for 30min. The reaction mixture was diluted with water (20 mL), and theorganic layer was separated. The aqueous layer was extracted with EtOAc(5 mL×3). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography on silica gel using MeOH in DCM (10%) to give thetitle compound (32.0 mg, 0.111 mmol, 74.9% yield) as a dark green solid.LCMS calc. for C₁₀H₁₂BrN₂OS [M+H]⁺: m/z=287.0, 289.0; Found: 287.0,288.9.

Step 4.6-(2-Chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one

A mixture of hexamethylditin (58.0 μL, 0.280 mmol),6-bromo-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one (40.0 mg,0.140 mmol), and tetrakis (triphenylphosphine)palladium(0) (24.1 mg,0.0200 mmol) in 1,4-dioxane (5.00 mL) was heated at 100° C. for 1 h. Thereaction mixture was cooled to room temperature, and2,6-dichloro-5-fluoracil (69.8 mg, 0.420 mmol) was added to the mixture.The reaction mixture was then heated at 100° C. for 18 h. The reactionmixture was cooled to room temperature, and a solution of potassiumfluoride (16.2 mg, 0.280 mmol) in water (2.0 mL) was added. The reactionmixture was stirred for 10 min. The mixture was filtered through a padof Celite, and the organic layer was separated. The aqueous layerextracted with EtOAc (5 mL×2). The combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel using MeOH inDCM (10%) to give the title compound (25.0 mg, 0.070 mmol, 53.0% yield)as an off-white solid. LCMS calc. for C₁₄H₁₃ClFN₄OS [M+H]⁺: m/z=339.0;Found: 338.9.

Step 5.6-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one

A suspension of6-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one(20.0 mg, 0.060 mmol),5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridine-2-amine (12.9 mg,0.060 mmol),(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (7.50 mg, 8.90 μmol), and cesium carbonate (38.5 mg,0.12 mmol) in 1,4-dioxane (1.50 mL) was heated to 100° C. for 18 hours.Upon cooling to room temperature, TFA (27.1 μL, 0.350 mmol) was added.The inorganic salts were filtered off, and the filtrate was purified byprep-HPLC on C18 column (8-80% MeCN/0.1% TFA (aq.) to give the titlecompound as the TFA salt (6.60 mg, 8.80 μmol, 15% yield) as a yellowsolid. ¹H NMR (400 MHz, CD₃OD) δ 8.87-8.56 (m, 2H), 7.67 (dd, J=9.2, 2.7Hz, 1H), 7.55-7.37 (m, 2H), 4.67 (p, J=6.7 Hz, 1H), 4.51 (d, J=11.3 Hz,2H), 4.35-4.22 (m, 4H), 4.18 (s, 2H), 3.27 (q, J=7.4 Hz, 2H), 2.82 (d,J=3.2 Hz, 3H), 1.72 (d, J=6.6 Hz, 6H), 1.22 (t, J=7.2 Hz, 3H). LCMScalc. for C₂₆H₃₀FN₈OS [M+H]⁺: m/z=521.2; Found: 521.1.

Example 632-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one

Step 1. 7-Isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one

Lithium diisopropylamide (4.40 mL, 8.80 mmol, 2.0 M inTHF/n-heptane/ethylbenzene) was added dropwise over 10 min to a solutionof 4-methyl-3-thiophenecarboxylic acid (569 mg, 4.00 mmol) in THE (6.00mL) at 0° C. To the reaction mixture was added a solution ofN-methoxy-N,2-dimethylpropanamide (0.611 mL, 4.40 mmol) in THE (3.00 mL)dropwise over 10 min at 0° C. The reaction mixture was warmed to roomtemperature and was stirred for 2 h. The reaction mixture was pouredinto water (10 mL), and the organic layer was separated. The aqueouslayer was washed with EtOAc (20 mL) and acidified with 1N HCl (5 mL).The aqueous layer was extracted again with EtOAc (20 mL×2). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated. The crude residue containing2-isobutyryl-4-methylthiophene-3-carboxylic acid was used in the nextstep without further purification.

Methylhydrazine (0.150 mL, 2.93 mmol) was added to a solution of crude2-isobutyryl-4-methylthiophene-3-carboxylic acid (415 mg) in ethanol(19.6 mL) at room temperature. The reaction mixture was at heated to 80°C. for 18 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The crude residue was purified bysilica gel chromatography (0-30% EtOAc/hexanes) to give the titlecompound (362 mg, 1.63 mmol, 83.0% yield). ¹H NMR (400 MHz, CDCl₃) δ7.16 (s, 1H), 3.82 (s, 3H), 3.12 (p, J=8.0 Hz, 1H), 2.70 (s, 3H), 1.37(d, J=8.0 Hz, 6H). LCMS calc. for C₁₁H₁₅N₂OS [M+H]⁺: m/z=223.1; Found:223.0.

Step 2. 2-Bromo-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one

N-Bromosuccinimide (304 mg, 1.71 mmol) was added to a solution of7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one (362 mg, 1.63mmol) in acetonitrile (8.1 mL) at room temperature. The reaction mixturewas stirred for 18 h. The reaction mixture was diluted with water (10mL), and the organic layer was separated. The aqueous layer extractedwith DCM (10 mL×3). The combined organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography on silica gel using EtOAc in hexanes(10%) to give title compound (350 mg, 1.16 mmol, 71.0% yield). LCMScalc. for C₁₁H₁₄BrN₂OS [M+H]⁺: m/z=301.0, 303.0; Found: 300.9, 302.9.

Step 3.2-(2-Chloro-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one

The title compound is synthetized by a procedure analogous to thatoutline in Example 62, Step 4. LCMS calc. for C₁₅H₁₅ClFN₄OS [M+H]⁺:m/z=353.1, 355.0; Found: 352.9, 355.0

Step 5.2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one

The title is synthesized by a procedure analogous to that outline inExample 62, Step 5. Purification by prep-HPLC on a C18 column (20-40%MeCN/0.1% TFA (aq.)) afforded the title compound as the TFA salt (17.8mg, 0.020 mmol, 26.0% yield), a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 10.18 (s, 1H), 9.76 (s, 1H), 8.76 (d, J=2.4 Hz, 1H), 7.85 (d, J=9.0Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.12 (dd, J=9.0, 2.9 Hz, 1H), 4.34 (dd,J=11.6, 6.3 Hz, 2H), 4.20 (dd, J=11.6, 6.0 Hz, 2H), 4.08 (s, 2H), 3.98(s, 2H), 3.71 (s, 3H), 3.26-3.07 (m, 3H), 2.69 (d, J=3.1 Hz, 3H), 1.34(d, J=6.9 Hz, 6H), 1.06 (s, 3H). LCMS calc. for C₂₇H₃₂FN₈OS [M+H]⁺:m/z=535.2; Found: 535.1.

Examples 64-75

Examples listed in Tables 5-1 and 5-2 are synthesized according toprocedures analogous to Example 1.

TABLE 5-1 Examples 64-75 Ex- am- LCMS ple R₁ R₂ R₃ [M + H]⁺ 64 H iso-propyl

531.0 65 H iso- propyl

523.2 66 Me iso- propyl H 383.0 67 Me iso- propyl

492.9 68 Me iso- propyl

491.9 69 Me iso- propyl

544.9 70 Me iso- propyl

542.8 71 H iso- propyl

520.9 72 H iso- propyl

466.8 73 Me iso- propyl

494.7 74 H iso- propyl

493.0 75 Me iso- propyl

495.0

TABLE 5-2 Examples 64-75 Example Compound name NMR 64 N-[5-[[4-(2,2- ¹HNMR (300 MHz, CD₃OD) δ 8.78 (d, J = Difluoroethyl)piperazin-1- 3.1 Hz,1H), 8.53 (d, J = 2.0 Hz, 1H), yl]methyl]pyridin-2-yl]-5- 8.35 (dd, J =9.0, 2.1 Hz, 1H), 8.17 (d, J = fluoro-4-(2-methyl-3-propan-2- 1.0 Hz,1H), 7.80 (d, J = 8.9 Hz, 1H), 6.07 ylthieno[2,3-d]imidazol-5- (tt, J =55.3, 4.0 Hz, 1H), 5.11-4.91 (m, yl)pyrimidin-2-amine, TFA salt 1H),4.36 (s, 2H), 3.36-3.30 (m, 4H), 3.10-2.99 (m, 6H), 2.90 (s, 3H), 1.71(d, J = 6.6 Hz, 6H). 65 1-[[6-[[5-Fluoro-4-(2-methyl-3- ¹H NMR (300 MHz,CD₃OD) δ 8.68 (d, J = propan-2-ylthieno[2,3- 3.2 Hz, 1H), 8.53 (d, J =2.2 Hz, 1H), d]imidazol-5-yl)pyrimidin-2- 8.30 (d, J = 8.8 Hz, 1H), 8.16(dd, J = 8.9, yl]amino]pyridin-3-yl]methyl]- 2.3 Hz, 1H), 8.10 (d, J =1.1 Hz, 1H), 5.02- N,N-dimethylpyrrolidine-3- 4.98 (m, 1H), 4.55 (d, J =8.2 Hz, 2H), carboxamide, TFA salt 3.77 (s, 2H), 3.62-3.47 (m, 3H), 3.15(s, 3H), 3.01 (s, 3H), 2.86 (s, 3H), 2.23 (t, J = 7.6 Hz, 1H), 2.07 (d,J = 5.8 Hz, 1H), 1.73 (d, J = 6.6 Hz, 6H). 664-(2,6-Dimethyl-3-propan-2- ¹H NMR (400 MHz, DMSO-d₆) δ 11.37ylthieno[2,3-d]imidazol-5-yl)-5- (s, 1H), 8.81 (d, J = 3.0 Hz, 1H), 8.40(d, J = fluoro-N-pyridin-2-ylpyrimidin- 5.7 Hz, 1H), 8.13 (t, J = 8.3Hz, 1H), 2-amine, TFA salt 7.90 (d, J = 8.7 Hz, 1H), 7.28 (t, J = 6.5Hz, 1H), 4.85 (p, J = 6.8 Hz, 1H), 2.72 (s, 3H), 2.62 (d, J = 3.5 Hz,3H), 1.54 (d, J = 6.6 Hz, 6H). 67 4-(2,6-Dimethyl-3-propan-2- ¹H NMR(300 MHz, CD₃OD) δ 8.73 (d, J = ylthieno[2,3-d]imidazol-5-yl)-5- 3.1 Hz,1H), 7.74 (dd, J = 9.2, 3.0 Hz, fluoro-N-[5-(1-methyl-1,6- 1H),7.61-7.56 (m, 2H), 5.01-4.92 (m, diazaspiro[3.3]heptan-6- 1H), 4.59 (d,J = 8.6 Hz, 2H), 4.25 (d, J = yl)pyridin-2-yl]pyrimidin-2-amine, 10.0Hz, 2H), 4.09 (s, 2H), 3.07 (s, 3H), TFA salt 2.88 (t, J = 6.1 Hz, 2H),2.85 (s, 3H), 2.74 (d, J = 3.0 Hz, 3H), 1.67 (d, J = 6.7 Hz, 6H). 684-(2,6-Dimethyl-3-propan-2- ¹H NMR (300 MHz, CD₃OD) δ 8.74 (d, J =ylthieno[2,3-d]imidazol-5-yl)-N- 3.1 Hz, 1H), 8.13 (dd, J = 9.7, 3.0 Hz,[5-(4-ethyl-6,6-difluoro-1,4- 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.58 (d, J= diazepan-1-yl)pyridin-2-yl]-5- 9.7 Hz, 1H), 5.01-4.92 (m, 1H), 4.17(t, J = fluoropyrimidin-2-amine, TFA 12.4 Hz, 2H), 3.86 (t, J = 5.6 Hz,2H), salt 3.66 (t, J = 12.7 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 3.21 (q,J = 13.6, 6.4 Hz, 2H), 2.85 (s, 3H), 2.73 (d, J = 3.0 Hz, 3H), 1.67 (d,J = 6.7 Hz, 6H), 1.31 (t, J = 7.2 Hz, 3H). 694-(2,6-Dimethyl-3-propan-2- ¹H NMR (300 MHz, CD₃OD) δ 8.75 (d, J =ylthieno[2,3-d]imidazol-5-yl)-5- 3.2 Hz, 1H), 8.22 (dd, J = 9.6, 3.0 Hz,fluoro-N-[5-[2,2,3,3,5,5,6,6- 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.63 (d, J= octadeuterio-4- 9.6 Hz, 1H), 4.96 (dd, J = 8.3, 4.9 Hz,(trideuteriomethyl)piperazin-1- 1H), 2.85 (s, 3H), 2.74 (d, J = 3.0 Hz,3H), yl]pyridin-2-yl]pyrimidin-2- 1.67 (d, J = 6.7 Hz, 6H). amine, TFAsalt 70 N-[5-(5,5-Difluoro-7-methyl- ¹H NMR (300 MHz, CD₃OD) δ 8.72 (d,J = 2,7-diazaspiro[3.4]octan-2- 3.2 Hz, 1H), 7.73 (dd, J = 9.5, 2.7 Hz,yl)pyridin-2-yl]-4-(2,6-dimethyl- 1H), 7.56 (dd, J = 6.1, 3.1 Hz, 2H),5.01- 3-propan-2-ylthieno[2,3- 4.89 (m, 1H), 4.33 (d, J = 8.2 Hz, 2H),d]imidazol-5-yl)-5- 4.06 (d, J = 8.2 Hz, 2H), 3.98-3.86 (m,fluoropyrimidin-2-amine, TFA 4H), 2.98 (s, 3H), 2.83 (d, J = 1.6 Hz,3H), salt 2.73 (d, J = 3.0 Hz, 3H), 1.67 (d, J = 6.7 Hz, 6H). 71(6-Dthyl-2,6- ¹H NMR (300 MHz, DMSO-d₆) δ 10.46diazaspiro[3.3]heptan-2-yl)-[6- (s, 1H), 9.70 (s, 1H), 8.70 (d, J = 3.3Hz, [[5-fluoro-4-(2-methyl-3- 1H), 8.54 (s, 1H), 8.28 (d, J = 8.8 Hz,1H), propan-2-ylthieno[2,3- 8.07 (dd, J = 8.8, 2.4 Hz, 1H), 7.97 (d, J =d]imidazol-5-yl)pyrimidin-2- 1.3 Hz, 1H), 4.79 (hept, J = 6.4, 6.0 Hz,yl]amino]pyridin-3- 1H), 4.58 (d, J = 27.4 Hz, 2H), 4.37-4.25yl]methanone, TFA salt (m, 4H), 4.24-4.15 (m, 2H), 3.19-3.09 (m, 2H),2.63 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H), 1.04 (t, J = 7.1 Hz, 3H). 72N-[5-[3-(Dimethylamino)azetidin- ¹H NMR (300 MHz, CD₃OD) δ 8.68 (d, J =1-yl]pyridin-2-yl]-5- 3.3 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H),fluoro-4-(2-methyl-3-propan-2- 7.72 (dd, J = 9.2, 3.0 Hz, 1H), 7.59-7.53ylthieno[2,3-d]imidazol-5- (m, 2H), 4.96 (d, J = 6.5 Hz, 1H), 4.35yl)pyrimidin-2-amine, TFA salt (dq, J = 10.3, 5.1, 3.6 Hz, 3H), 4.23(dd, J = 7.8, 3.5 Hz, 2H), 2.98 (s, 6H), 2.81 (s, 3H), 1.68 (d, J = 6.7Hz, 6H). 73 N-[5-[3-(Dimethylamino)pyrrolidin- ¹H NMR (300 MHz, CD₃OD) δ8.75 (d, J = 1-yl]pyridin-2-yl]-4- 3.1 Hz, 1H), 7.91 (dd, J = 9.6, 3.0Hz, (2,6-dimethyl-3-propan-2- 1H), 7.62 (d, J = 2.9 Hz, 1H), 7.56 (d, J= ylthieno[2,3-d]imidazol-5-yl)-5- 9.5 Hz, 1H), 4.97 (t, J = 6.7 Hz,1H), 4.13 fluoropyrimidin-2-amine, TFA (q, J = 7.2 Hz, 1H), 3.83 (dd, J= 10.6, 7.4 salt Hz, 1H), 3.75-3.66 (m, 2H), 3.52-3.42 (m, 1H), 3.02 (s,6H), 2.86 (s, 3H), 2.74 (d, J = 3.0 Hz, 3H), 2.69-2.63 (m, 1H),2.46-2.35 (m, 1H), 1.68 (d, J = 6.6 Hz, 6H). 74 N-[5-(6-ethyl-3,6- ¹HNMR (300 MHz, CD₃OD) δ 8.71 (d, J = Diazabicyclo[3.1.1]heptan-3- 3.3 Hz,1H), 8.13 (d, J = 1.1 Hz, 1H), yl)pyridin-2-yl]-5-fluoro-4-(2- 8.06 (dt,J = 9.7, 3.0 Hz, 1H), 7.80 (d, J = methyl-3-propan-2-ylthieno[2,3- 3.0Hz, 1H), 7.62 (d, J = 9.6 Hz, 1H), 4.72 d]imidazol-5-yl)pyrimidin-2- (d,J = 6.3 Hz, 1H), 4.58 (d, J = 6.4 Hz, amine, TFA salt 1H), 4.15-3.84 (m,4H), 3.59 (q, J = 8.0, 7.5 Hz, 1H), 3.48-3.20 (m, 2H), 3.10 (p, J = 7.2Hz, 1H), 2.82 (s, 3H), 2.28-2.11 (m, 1H), 1.68 (d, J = 6.6 Hz, 6H),1.44- 1.33 (m, 3H). 75 1-[6-[[4-(2,6-Dimethyl-3- ¹H NMR (400 MHz,DMSO-d₆) δ 10.34 propan-2-ylthieno[2,3- (s, 1H), 8.73 (d, J = 3.0 Hz,1H), 8.30 (d, J = d]imidazol-5-yl)-5- 2.7 Hz, 1H), 8.24 (d, J = 9.0 Hz,1H), fluoropyrimidin-2- 7.79 (dd, J = 9.0, 2.7 Hz, 1H), 4.83 (p, J =yl]amino]pyridin-3-yl]-4- 6.6 Hz, 1H), 4.17-4.03 (m, 2H), 3.94 (t, J =methylpiperazin-2-one, TFA salt 5.6 Hz, 2H), 3.77-3.58 (m, 2H), 2.97 (s,3H), 2.70 (s, 3H), 2.57 (d, J = 3.7 Hz, 3H), 1.54 (d, J = 6.6 Hz, 6H).

Examples 76-92

Examples listed in Tables 6-1 and 6-2 are synthesized according toprocedures analogous to Example 51 and Example 56.

TABLE 6-1 Examples 76-92. Ex- am- LCMS ple R¹ R² R³ [M + H]⁺ 76 Me Me

548.2 77 Me Me

548.1 78 Me Me

534.1 79 Me Me

534.2 80 Me Me

576.3 81 Me H

520.0 82 Me Me

510.0 83 Me Me

534.3 84 Me Me

563.2 85 CD₃ Me

510.2 86 Me H

493.0 87 Me Me

521.0 88 Me Me

507.0 89 Me Me

536.2 90 Me Me

536.2 91 Me Me

548.2 92 Me Me

547.9

TABLE 6-2 Examples 76-92. Example Compound name NMR 762-(5-Fluoro-2-((5-(7-methyl- — 2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin- 4-yl)-7-isopropyl-3,5-dimethylthieno[3,2- c]pyridin-4(5H)-one, TFA salt 772-(5-Fluoro-2-((5-(7-methyl- ¹H NMR (400 MHz, DMSO-d₆) δ 8.742,7-diazaspiro[3.5]nonan-2- (d, J = 2.7 Hz, 1H), 7.68 (dd, J = 9.5,yl)pyridin-2-yl)amino)pyrimidin- 2.8 Hz, 1H), 7.53-7.42 (m, 3H), 3.914-yl)-7-isopropyl- (s, 2H), 3.81 (s, 2H), 3.63 (s, 3H), 3.58-3,5-dimethylthieno[3,2- 3.42 (m, 2H), 3.20-2.95 (m, 3H),c]pyridin-4(5H)-one, TFA 2.91 (s, 3H), 2.84 (d, J = 3.2 Hz, 3H), salt2.29 (d, J = 14.6 Hz, 2H), 2.15-1.98 (m, 2H), 1.40 (d, J = 6.9 Hz, 6H).78 2-(5-Fluoro-2-((5- ¹H NMR (400 MHz, DMSO-d₆) δ ((3aR,6aS)-5- 10.68(d, J = 7.7 Hz, 1H), 10.05 (bs, methylhexahydropyrrolo[3,4- 0.5H), 9.83(bs, 0.5H), 8.76 (d, J = 2.5 c]pyrrol-2(1H)-yl)pyridin-2- Hz, 1H), 7.84(d, J = 9.2 Hz, 1H), 7.76 yl)amino)pyrimidin-4-yl)-7- (dd, J = 11.2, 2.9Hz, 1H), 7.63-7.48 isopropyl-3,5-dimethylthieno[3,2- (m, 2H), 3.98-3.77(m, 1H), 3.60- c]pyridin-4(5H)-one, 3.43 (m, 5H), 3.42-3.23 (m, 4H),3.17- TFA salt 3.03 (m, 2H), 2.97-2.78 (m, 5H), 2.71 (d, J = 3.3 Hz,3H), 1.31 (d, J = 6.8 Hz, 6H). 79 2-(5-Fluoro-2-((5- ¹H NMR (300 MHz,methanol-d₄) δ ((3aS,6aS)-5- 8.73 (d, J = 2.6 Hz, 1H), 7.80 (dd, J =methylhexahydropyrrolo[3,4- 9.6, 3.0 Hz, 1H), 7.54-7.41 (m, 3H),c]pyrrol-2(1H)-yl)pyridin-2- 4.06-3.91 (m, 1H), 3.75-3.34 (m,yl)amino)pyrimidin-4-yl)-7- 5H), 3.63 (s, 3H), 3.14-2.86 (m, 3H),isopropyl-3,5-dimethylthieno[3,2- 3.07 (s, 3H), 2.83 (d, J = 3.2 Hz,3H), c]pyridin-4(5H)-one, 2.79-2.52 (m, 2H), 1.39 (d, J = 6.9 Hz, TFAsalt 6H). 80 2-(5-Fluoro-2-((5-(4-(2,2,2- — trifluoroethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin- 4-yl)-7-isopropyl-3,5-dimethylthieno[3,2- c]pyridin-4(5H)-one, TFA salt 812-(2-((5-(5-Ethyl-2,5- ¹H NMR (300 MHz, methanol-d₄) δdiazabicyclo[2.2.1]heptan-2- 8.69 (d, J = 3.3 Hz, 1H), 8.50 (d, J =yl)pyridin-2-yl)amino)-5- 1.7 Hz, 1H), 7.92 (dd, J = 9.6, 3.0 Hz,fluoropyrimidin-4-yl)-7- 1H), 7.66 (d, J = 2.9 Hz, 1H), 7.57-isopropyl-5-methylthieno[3,2- 7.45 (m, 2H), 4.85-4.70 (m, 2H), 4.59c]pyridin-4(5H)-one, bs, 1H), 3.96-3.71 (m, 2H), 3.65 (s, TFA salt 3H),3.61-3.33 (m, 3H), 3.12-2.94 (m, 1H), 2.52-2.25 (m, 2H), 1.42 (d, J =6.9 Hz, 6H), 1.36 (t, J = 7.2 Hz, 3H). 82 2-(5-Fluoro-2-((5-(1- ¹H NMR(300 MHz, methanol-d₄) δ (methyl-d3)piperidin-4- 8.81 (d, J = 2.7 Hz,1H), 8.35-8.26 yl)pyridin-2-yl)amino)pyrimidin- (m, 2H), 7.64 (d, J =9.0 Hz, 1H), 7.47 4-yl)-7-isopropyl- (s, 1H), 3.75-3.65 (m, 2H), 3.64(s, 3,5-dimethylthieno[3,2- 3H), 3.30-2.98 (m, 4H), 2.86 (d, J =c]pyridin-4(5H)-one, TFA 3.3 Hz, 3H), 2.30-2.20 (m, 2H), 2.15- salt 1.96(m, 2H), 1.40 (d, J = 6.9 Hz, 6H). 83 2-(2-((5-(1,4- —Diazabicyclo[3,2.2]nonan-4- yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7- isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one, TFA salt 84 2-(5-Fluoro-2-((5-(1- ¹H NMR (300 MHz,Methanol-d₄) δ (tetrahydrofuran-3- 8.81 (d, J = 2.6 Hz, 1H), 8.55-8.10yl)piperidin-4-yl)pyridin-2- (m, 2H), 7.61 (d, J = 9.0 Hz, 1H), 7.46yl)amino)pyrimidin-4-yl)-7- (s, 1H), 4.32-4.17 (m, 1H), 4.16-isopropyl-3,5-dimethylthieno[3,2- 4.00 (m, 2H), 3.89 (dd, J = 11.0, 6.3c]pyridin-4(5H)-one, Hz, 1H), 3.83-3.56 (m, 6H), 3.31- TFA salt 3.07 (m,3H), 3.00 (p, J = 6.9 Hz, 1H), 2.85 (d, J = 3.2 Hz, 3H), 2.57-2.36 (m,1H), 2.34-2.20 (m, 3H), 2.19- 2.00 (m, 2H), 1.39 (d, J = 6.9 Hz, 6H). 852-(5-Fluoro-2-((5-(1- ¹H NMR (300 MHz, methanol-d₄) δ methylpiperidin-4-8.74 (d, J = 2.6 Hz, 1H), 8.27-8.20 yl)pyridin-2-yl)amino)pyrimidin- (m,2H), 7.58 (d, J = 8.9 Hz, 1H), 7.40 4-yl)-7-isopropyl- (s, 1H), 3.63 (d,J = 12.6 Hz, 2H), 3.20- 3-methyl-5-(methyl- 3.07 (m, 3H), 2.98-2.92 (m,1H), d3)thieno[3,2-c]pyridin- 2.89 (s, 3H), 2.80 (d, J = 3.2 Hz, 3H),4(5H)-one, TFA salt 2.24-2.12 (m, 2H), 2.07-1.93 (m, 2H), 1.34 (d, J =6.9 Hz, 6H). 86 2-(5-Fluoro-2-((5-(1- ¹H NMR (300 MHz, methanol-d₄) δmethylpiperidin-4- 8.77 (d, J = 3.2 Hz, 1H), 8.55 (d, J =yl)pyridin-2-yl)amino)pyrimidin- 1.5 Hz, 1H), 8.36-8.26 (m, 2H), 7.614-yl)-7-isopropyl- (d, J = 9.0 Hz, 1H), 7.52 (s, 1H), 3.80-5-methylthieno[3,2- 3.55 (m, 5H), 3.26-3.17 (m, 2H), 3.11-c]pyridin-4(5H)-one, TFA 3.02 (m, 2H), 2.96 (s, 3H), 2.25 salt (d, J =14.1 Hz, 2H), 2.15-1.95 (m, 2H), 1.43 (d, J = 6.9 Hz, 6H). 872-(2-((5-(1-Ethylpiperidin-4- ¹H NMR (300 MHz, DMSO-d₆) δyl)pyridin-2-yl)amino)-5- 10.09 (s, 2H), 8.73 (d, J = 2.5 Hz, 1H),fluoropyrimidin-4-yl)-7- 8.20 (s, 1H), 8.15 (d, J = 8.7 Hz, 1H),isopropyl-3,5- 7.65 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H),dimethylthieno[3,2- 3.51 (s, 3H), 3.20-2.74 (m, 8H), 2.69c]pyridin-4(5H)-one, HCl (d, J = 3.5 Hz, 3H), 2.20-1.80 (s, 4H), salt1.31 (d, J = 6.8 Hz, 6H), 1.28-1.20 (m, 3H). 88 2-(5-Fluoro-2-((5-(1- ¹HNMR (300 MHz, methanol-d₄) δ methylpiperidin-3- 8.76 (d, J = 2.6 Hz,1H), 8.27 (d, J = yl)pyridin-2-yl)amino)pyrimidin- 2.2 Hz, 1H), 8.19(dd, J = 9.1, 2.1 Hz, 4-yl)-7-isopropyl- 1H), 7.77 (d, J = 9.0 Hz, 1H),7.45 (s, 3,5-dimethylthieno[3,2- 1H), 3.71-3.55 (m, 5H), 3.23-3.14c]pyridin-4(5H)-one, TFA (m, 2H), 3.08-2.97 (m, 2H), 2.94 (s, salt 3H),2.83 (d, J = 3.3 Hz, 3H), 2.22- 2.05 (m, 2H), 2.04-1.72 (m, 2H), 1.39(d, J = 6.9 Hz, 6H). 89 2-(5-Fluoro-2-((5-(4- ¹H NMR (400 MHz,methanol-d₄) δ isopropylpiperazin-1- 8.79 (d, J = 2.6 Hz, 1H), 8.27 (dd,J = yl)pyridin-2-yl)amino)pyrimidin- 9.7, 2.9 Hz, 1H), 7.92 (d, J = 2.8Hz, 4-yl)-7-isopropyl- 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.45 (s,3,5-dimethylthieno[3,2- 1H), 3.97 (d, J = 12.1 Hz, 2H), 3.76-c]pyridin-4(5H)-one, HCl 3.58 (m, 6H), 3.42-3.21 (m, 4H), 3.00 salt(sept, J = 6.9 Hz, 1H), 2.85 (d, J = 3.2 Hz, 3H), 1.46 (d, J = 6.7 Hz,6H), 1.39 (d, J = 6.9 Hz, 6H). 90 2-(2-((5-((4-Ethylpiperazin- ¹H NMR(300 MHz, methanol-d₄) δ 1-yl)methyl)pyridin-2- 8.81 (d, J = 2.6 Hz,1H), 8.40-8.30 yl)amino)-5-fluoropyrimidin- (m, 2H), 7.62 (d, J = 9.7Hz, 1H), 7.47 4-yl)-7-isopropyl-3,5- (s, 1H), 3.76 (s, 2H), 3.64 (s,3H), 3.32- dimethylthieno[3,2- 2.95 (m, 11H), 2.86 (d, J = 3.2 Hz,c]pyridin-4(5H)-one, TFA salt 3H), 1.4-1.25 (m, 9H). 912-(5-Fluoro-2-((5-(2-methyl- ¹H NMR (300 MHz, methanol-d₄) δ2,7-diazaspiro[3.5]nonan-7- 8.74 (d, J = 2.6 Hz, 1H), 8.19 (dd, J =yl)pyridin-2-yl)amino)pyrimidin- 9.7, 2.9 Hz, 1H), 7.79 (d, J = 2.8 Hz,4-yl)-7-isopropyl- 1H), 7.48 (d, J = 9.7 Hz, 1H), 7.44 (s,3,5-dimethylthieno[3,2- 1H), 4.19 (d, J = 11.2 Hz, 2H), 3.92 (d,c]pyridin-4(5H)-one, TFA J = 11.2 Hz, 2H), 3.62 (s, 3H), 3.28- salt 3.15(m, 3H), 3.09-2.91 (m, 5H), 2.83 (d, J = 3.2 Hz, 3H), 2.13-1.96 (m, 4H),1.38 (d, J = 6.9 Hz, 6H). 92 2-(5-Fluoro-2-((5-(6- ¹H NMR (300 MHz,DMSO-d₆) δ isopropyl-2,6- 10.53 (s, 1H), 10.36-10.07 (m, 1H),diazaspiro[3.3]heptan-2- 8.73 (d, J = 2.6 Hz, 1H), 7.81 (d, J =yl)pyridin-2-yl)amino)pyrimidin- 9.1 Hz, 1H), 7.66-7.46 (m, 2H), 7.294-yl)-7-isopropyl- (dd, J = 9.1, 2.7 Hz, 1H), 4.29 (d, J =3,5-dimethylthieno[3,2- 6.3 Hz, 4H), 4.12 (s, 2H), 3.98 (s, 2H),c]pyridin-4(5H)-one, TFA 3.52 (s, 3H), 3.48-3.31 (m, 1H), 2.89 salt (p,J = 6.8 Hz, 1H), 2.70 (d, J = 3.2 Hz, 3H), 1.31 (d, J = 6.8 Hz, 6H),1.12 (d, J = 6.4 Hz, 6H).

Example 932-(5-Fluoro-2-((6-(1-methylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

Step 1. tert-Butyl4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate

N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (2.63 g,8.49 mmol), 6-chloropyridazin-3-amine (1.00 g, 7.72 mmol), K₃PO₄ (4.92g, 23.2 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.565 g, 0.772 mmol)were suspended in 1,4-dioxane (15.0 mL) and water (5.00 mL) under inertatmosphere. The reaction mixture was heated at 100° C. for 2 h. Thereaction mixture was cooled to room temperature and diluted with water(30.0 mL). The mixture was extracted with EtOAc (30.0 mL×3). The organiclayers were combined, dried over sodium sulfate, filtered, andconcentrated. The crude material was suspended in DCM (20.0 mL), and thesolid was collected by filtration to afford the title compound (1.65 g,5.97 mmol, 77.4% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 7.39(d, J=9.3 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 6.32 (s, 1H), 4.69 (s, 2H),4.12 (q, J=3.1 Hz, 2H), 3.64 (t, J=5.7 Hz, 2H), 2.76 (s, 2H), 1.49 (s,9H).

Step 2. tert-Butyl 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylate

tert-Butyl4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.60 g,5.79 mmol) was dissolved in MeOH (30.0 mL). Palladium on carbon (0.800g, 0.751 mmol, 10 wt %) and acetic acid (2.00 mL, 34.8 mmol) were addedsequentially. The reaction vessel was sealed in a Parr shaker, and thevessel was charged with H₂ (60 psi). The reaction mixture was shakenovernight. The atmosphere of hydrogen was removed, the mixture wasfiltered, and the filtrate was concentrated under reduced pressure. Thecrude residue was purified by silica gel chromatography (50-100% EtOAcin heptanes, then 0-30% MeOH in EtOAc to afford the title compound (610mg, 2.19 mmol, 37.8% yield). LCMS calc. for C₁₄H₂₃N₄O₂ [M+H]+:m/z=279.2; Found: 279.0.

Step 3. 6-(Piperidin-4-yl)pyridazin-3-amine

tert-Butyl4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (610 mg,2.19 mmol) was dissolved in DCM (6.00 mL), and trifluoroacetic acid(6.00 mL, 78.4 mmol) was added slowly at room temperature. The reactionmixture was stirred for 18 h. The reaction mixture was concentratedunder reduced pressure, and crude residue was azeotroped with toluene(5.00 mL×3). The crude residue was used without further purification toafford the crude TFA salt of the title compound (1.10 g) as apale-yellow oil. LCMS calc. for C₉H₁₅N₄[M+H]+: m/z=179.1; Found: 179.0.

Step 4. 6-(1-Methylpiperidin-4-yl)pyridazin-3-amine

Formaldehyde (1.10 mL, 14.8 mmol, 37 wt % in H2O), acetic acid (0.845mL, 14.8 mmol), and the crude TFA salt of6-(piperidin-4-yl)pyridazin-3-amine (1.10 g) were dissolved in MeOH(20.0 mL) at room temperature. Sodium cyanoborohydride (0.928 g, 14.8mmol) was added portion-wise, and the reaction mixture was stirredovernight. The reaction was quenched with water (100 mL), and thereaction mixture diluted with EtOAc (100 mL). The organic phase wasseparated, and the aqueous layer was extracted with EtOAc (100 mL×3).The organic layers were combined, dried over sodium sulfate, filtered,and concentrated. The crude residue was purified by prep-HPLC using aC18 column (0-60% MeCN/0.1% TFA (aq.)) to afford a mixture of twocompounds. The fractions were collected and partially concentrated underreduced pressure. TFA (0.50 mL) was added to the solution. The solutionwas concentrated to dryness under reduced pressure. The crude residuewas further purified by prep-HPLC using a C18 column (0-60% MeCN/0.1%TFA (aq.)) to afford the TFA salt of the title compound (99.0 mg, 0.324mmol, 14.8% yield) as a yellow oil. ¹H NMR (300 MHz, Methanol-d₄) δ 7.87(d, J=9.5 Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 3.68 (d, J=12.3 Hz, 2H),3.27-3.05 (m, 3H), 2.95 (s, 3H), 2.30-2.22 (m, 2H), 2.06-1.95 (m, 2H).

Step 5.2-(5-Fluoro-2-((6-(1-methylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

The title compound is synthesized by procedures analogous to thoseoutlined in Example 1, Step 8. ¹H NMR (300 MHz, Methanol-d₄) δ 8.84 (d,J=2.5 Hz, 1H), 8.25 (d, J=9.4 Hz, 1H), 8.09 (d, J=9.4 Hz, 1H), 7.50 (s,1H), 3.74 (d, J=12.5 Hz, 2H), 3.67 (s, 3H), 3.33-3.20 (m, 3H), 3.08-3.01(m, 1H), 2.99 (s, 3H), 2.87 (d, J=3.3 Hz, 3H), 2.50-2.30 (m, 2H),2.25-2.11 (m, 2H), 1.43 (d, J=6.9 Hz, 6H). LCMS calc. for C₂₆H₃₁FN₇OS[M+H]+: m/z=508.2; Found: 507.9.

Example 94.2-(5-Fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

Step 1. tert-Butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate

The title compound is synthesized by procedures analogous to thoseoutlined in Example 93, Steps 1-2. LCMS calc. for C₁₅H₂₄N₃O₂ [M+H]+:m/z=278.2; Found: 278.0.

Step 2.2-(5-Fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

To a solution of2-(2-chloro-5-fluoropyrimidin-4-yl)-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one,TFA salt (40.0 mg, 0.0860 mmol, Example 51, Step 6) and tert-butyl4-(6-aminopyridin-3-yl)piperidine-1-carboxylate (37.8 mg, 0.136 mmol) in1,4-dioxane (1.00 mL) was added K3PO4 (111 mg, 0.341 mmol) and XPhos PdG2 (8.95 mg, 11.4 μmol, CAS 1310584-14-5). The reaction vessel wassealed, and the mixture was degassed with N2 (3×). The reaction mixturewas heated at 100° C. overnight. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue wasdissolved in DCM (20.0 mL) and washed with water (20.0 mL×2) and brine(20.0 mL×2). The organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure. The crude material wasdissolved in DCM (4.00 mL) and TFA (1.00 mL, 13.4 mmol) was added. Thereaction was stirred at room temperature for 30 min. The reactionmixture was concentrated under reduced pressure and the dark residue waspurified by prep-HPLC on a C18 column (0-60% MeCN/0.1% TFA (aq.))afforded the TFA salt of the title compound (47.2 mg, 0.0779 mmol, 90.6%yield). ¹H NMR (300 MHz, Methanol-d₄) δ 8.79 (d, J=2.6 Hz, 1H),8.32-8.22 (m, 2H), 7.67 (d, J=9.7 Hz, 1H), 7.46 (s, 1H), 3.63 (s, 3H),3.57 (d, J=13.0 Hz, 2H), 3.25-3.10 (m, 3H) 3.03-2.95 (m, 1H), 2.85 (d,J=3.2 Hz, 3H), 2.19 (d, J=12.8 Hz, 2H), 2.05-1.89 (m, 2H), 1.40 (d,J=6.9 Hz, 6H). LCMS calc. for C₂₆H₃₀N₆OS [M+H]+: m/z=493.2; Found:493.2.

Example 95.2-(5-Fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

Step 1.2-(5-Fluoro-2-((5-(pyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

The title compound is synthesized by procedures analogous to thoseoutlined in Example 94). LCMS calc. for C₂₅H₂₈FN₆OS [M+H]+: m/z=479.2;Found: 479.2.

Step 2.2-(5-Fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one

To a solution of tert-butyl3-(6-((5-fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-yl)amino)pyridin-3-yl)pyrrolidine-1-carboxylate(50.0 mg, 0.104 mmol) and acetone (31.0 μL, 0.418 mmol) in methanol(0.800 mL) was added sodium cyanoborohydride (32.8 mg, 0.552 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 1 h. The reaction mixture was concentrated under reduced pressureand the residue was purified by prep-HPLC on a C18 column (5-95%MeCN/0.1% TFA (aq.)) afforded the TFA salt of the title compound (44.0mg, 0.0694 mmol, 66.7% yield). ¹H NMR (300 MHz, Methanol-d₄) δ 8.77 (d,J=2.6 Hz, 1H), 8.46-8.32 (m, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.43 (s, 1H),4.10-3.48 (m, 8H), 3.40-3.23 (m, 1H), 3.04-2.75 (m, 1H), 2.83 (d, J=3.0Hz, 3H), 2.68-2.52 (m, 1H), 2.45-2.25 (m, 1H), 1.45 (d, J=6.5 Hz, 6H),1.37 (d, J=6.9 Hz, 6H). LCMS calc. for C₂₈H₃₄FN₆OS [M+H]+: m/z=521.3;Found: 521.2.

Example 96.7-Isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)pyridine-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one

Step 1.2-(2,5-Dichloropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one

The title compound is synthesized by a procedure analogous to thatoutline in Example 62, Step 4. LCMS calc. for C₁₅H₁₄Cl₂N₃OS [M+H]⁺:m/z=354.0; Found: 353.9.

Step 2.7-Isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one

The title is synthesized by a procedure analogous to that outline inExample 56, Step 6. Purification by prep-HPLC on a C18 column (10-30%MeCN/0.1% TFA (aq.)) afforded the TFA salt of the title compound as ayellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.75 (d, J=5.6 Hz, 1H),8.48 (s, 1H), 8.38-8.28 (m, 2H), 7.84 (d, J=5.6 Hz, 1H), 7.57 (d, J=8.9Hz, 1H), 7.48 (s, 1H), 3.75-3.55 (m, 2H), 3.65 (s, 3H), 3.30-2.96 (m,4H), 2.95 (s, 3H), 2.40-2.00 (m, 4H), 1.41 (d, J=6.9 Hz, 6H). LCMS calc.for C₂₆H₃₁N₆OS [M+H]⁺: m/z=475.2; Found: 475.3.

Example 97.7-Isopropyl-5-methyl-2-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one

Step 1.2-(2-Chloro-5-methylpyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one

The title compound is synthesized by a procedure analogous to thatoutline in Example 56, Step 5. LCMS calc. for C₁₆H₁₇ClN₃OS [M+H]⁺:m/z=334.1; Found: 334.0.

Step 2.7-Isopropyl-5-methyl-2-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one

The title is synthesized by a procedure analogous to that outline inExample 56, Step 6. Purification by prep-HPLC on a C18 column (2-40%MeCN/0.1% TFA (aq.)) afforded the title compound as the TFA salt, ayellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.66 (s, 1H), 8.40 (s,1H), 8.32-8.23 (m, 2H), 7.58 (d, J=9.8 Hz, 1H), 7.49 (s, 1H), 3.75-3.65(m, 2H), 3.67 (s, 3H), 3.28-2.97 (m, 4H), 2.96 (s, 3H), 2.70 (s, 3H),2.25 (d, J=14.1 Hz, 2H), 2.25-1.95 (m, 2H), 1.43 (d, J=6.9 Hz, 6H) LCMScalc. for C₂₇H₃₃N₆OS [M+H]⁺: m/z=489.2; Found: 489.2.

Example 98.4-(6-((5-Fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-1-methylpiperidine1-oxide

To a solution of2-(5-fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one(18.0 mg, 0.036 mmol, Example 56) in DCM (2.00 mL) was added m-CPBA(12.9 mg, 0.0750 mmol) at room temperature. The mixture was heated to100° C. for 3 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. Purification by prep-HPLC on a C18column (10-40% MeCN/0.1% TFA (aq.)) afforded the TFA salt of the titlecompound (12.0 mg, 0.019 mmol, 53.1% yield) as a yellow solid. ¹H NMR(300 MHz, Methanol-d₄) δ8.85 (d, J=2.6 Hz, 1H), 8.40-8.29 (m, 2H), 7.83(d, J=8.9 Hz, 1H), 7.54 (s, 1H), 4.06-3.85 (m, 4H), 3.72 (s, 3H), 3.69(s, 3H), 3.23-3.04 (m, 2H), 2.93 (d, J=3.3 Hz, 3H), 2.60-2.39 (m, 2H),2.22 (d, J=14.1 Hz, 2H), 1.48 (d, J=6.9 Hz, 6H). LCMS calc. forC₂₇H₃₂FN₆O₂S [M+H]⁺: m/z=523.2; Found: 523.2.

Example 99.5-Fluoro-4-(3-isopropyl-2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 55. Purification by silica gel chromatography usingMeOH in DCM (0-20%) afforded the free base of the title compound. Thesolvent was removed under reduced pressure and the residue was suspendedin MeOH (10.0 mL) and water (10.0 mL) then 2N HCl (2.50 mL) was added.The mixture was concentrated under reduced pressure to afford the HClsalt of the title compound (1.33 g, 2.47 mmol, 61.4% yield) as apale-yellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.76 (d, J=3.3 Hz,1H), 8.35 (dd, J=9.1, 2.3 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.04 (d,J=1.5 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 4.08 (s, 3H), 3.77-3.61 (m, 2H),3.39 (p, J=6.8 Hz, 1H), 3.29-3.02 (m, 3H), 2.95 (s, 3H), 2.24 (d, J=14.3Hz, 2H), 2.18-1.95 (m, 2H), 1.44 (d, J=6.8 Hz, 6H). LCMS calc. forC₂₄H₂₉FN₇S [M+H]⁺: m/z=466.2; Found: 466.0.

Example 100.N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine

Step 1.3-Iodo-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-thieno[3,2-c]pyrazoleand3-iodo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole

To a solution of 3-iodo-6-methyl-1H-thieno[3,2-c]pyrazole (1.17 mg, 4.43mmol, Example 55, Step 4) in 3,4-dihydro-2H-pyran (5.00 mL, 54.8 mmol)was added TFA (0.339 mL, 4.43 mmol) at room temperature. The reactionwas stirred at room temperature for 1 h. The crude reaction mixture waspurified directly by silica gel chromatography using EtOAc in hexanes(0-15%) to afford a mixture of the title compounds (1.21 g, 3.46 mmol,78.4% yield) as a colorless solid. Major isomer ¹H NMR (300 MHz, CDCl₃)δ 6.98 (d, J=1.2 Hz, 1H), 5.57 (dd, J=9.5, 2.6 Hz, 1H), 4.08-3.97 (m,1H), 3.78-3.61 (m, 1H), 2.64-2.43 (m, 1H), 2.42 (d, J=1.2 Hz, 3H),2.25-2.01 (m, 2H), 1.93-1.37 (m, 3H).

Step 2.6-Methyl-3-(prop-1-en-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-thieno[3,2-c]pyrazoleand6-methyl-3-(prop-1-en-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Step 1. Major isomer ¹H NMR (300 MHz, CDCl₃) δ6.97 (q, J=1.2 Hz, 1H), 5.62 (dd, J=9.4, 2.8 Hz, 1H), 5.40 (t, J=1.0 Hz,1H), 5.30-5.22 (m, 1H), 4.12-3.96 (m, 1H), 3.81-3.57 (m, 1H), 2.65-2.47(m, 1H), 2.45 (d, J=1.2 Hz, 3H), 2.24 (s, 3H), 2.23-2.01 (m, 2H),1.82-1.54 (m, 3H).

Step 3.3-Isopropyl-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-thieno[3,2-c]pyrazoleand3-isopropyl-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole

In a 100 mL reaction vessel, a mixture of3-isopropyl-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-thieno[3,2-c]pyrazoleand3-isopropyl-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole(661 mg, 2.52 mmol) was dissolved in MeOH (20.0 mL), and palladium oncarbon (100 mg, 0.094 mmol, 10 wt %) was added at room temperature. Thereaction vessel was sealed in a Parr shaker, and the vessel was chargedwith hydrogen (50 psi). The reaction mixture was shaken for 4 d. Theatmosphere of hydrogen was removed, the mixture was filtered, and thefiltrate was concentrated under reduced pressure. The crude residuecontaining a mixture of the title compounds (536 mg) was used withoutfurther purification

Step 4.3-Isopropyl-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole

A solution of lithium diisopropylamide (3.84 mL, 7.68 mmol, 2.0 M inTHF/heptane/ethylbenzene) was added to a mixture of3-isopropyl-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-thieno[3,2-c]pyrazoleand3-isopropyl-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-thieno[3,2-c]pyrazole(406 mg) in THE (2.00 mL) at −78° C. After stirring at −78° C. for 30min, tributyl(chloro)stannane (0.500 mL, 1.84 mmol) was added. Thereaction mixture was warmed to room temperature and stirred for 30 min.The reaction was quenched with sat. aq. NH₄Cl solution (2.00 mL), andthe reaction mixture was diluted with 3N aq. KF (2.00 mL). The mixturewas stirred at room temperature for 1 h and then filtered. The organiclayer was separated, and the aqueous layer was extracted with EtOAc(3.00 mL×2). The combined organic layers were dried over sodium sulfate,filtered, and concentrated. Purification by silica gel chromatographyusing EtOAc in hexanes (0-15%) afforded the title compound (401 mg,0.725 mmol, 47.2% yield) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ5.55 (dd, J=10.0, 2.5 Hz, 1H), 4.19-4.02 (m, 1H), 3.77-3.60 (m, 1H),3.13 (hept, J=7.0 Hz, 1H), 2.61-2.45 (m, 1H), 2.43 (s, 3H), 2.18-1.98(m, 2H), 1.93-1.01 (m, 27H), 0.90 (t, J=7.3 Hz, 9H).

Step 5.5-(2-Chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-thieno[3,2-c]pyrazole

To a solution of3-isopropyl-6-methyl-2-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole(401 mg, 0.724 mmol) in toluene (1.00 mL) was added2,4-dichloro-5-fluoropyrimidine (252 mg, 1.45 mmol) andtetrakis(triphenylphosphine)palladium(0) (125 mg, 0.109 mmol). Thereaction vessel was sealed, and the mixture was degassed with N₂ (3×).The reaction mixture was heated at 100° C. overnight. The reactionmixture was cooled to room temperature and purified by silica gelchromatography using EtOAc in heptanes (0-10%) to afford the titlecompound (142 mg, 0.359 mmol, 49.6% yield) as a colorless solid. ¹H NMR(300 MHz, CDCl₃) δ 8.52 (d, J=2.4 Hz, 1H), 5.64 (dd, J=9.7, 2.5 Hz, 1H),4.11-4.01 (m, 2H), 3.82-3.56 (m, 1H), 2.66 (d, J=3.0 Hz, 3H), 2.62-2.40(m, 1H), 2.35-1.96 (m, 2H), 1.88-1.58 (m, 3H), 1.38 (d, J=3.4 Hz, 3H),1.36 (d, J=3.4 Hz, 3H).

Step 6.N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 1, Step 8. The crude residue was purified byprep-HPLC on a C18 column (2-50% MeCN/0.1% TFA (aq.)) to afford the TFAsalt of the title compound as a yellow solid. ¹H NMR (300 MHz,Methanol-d₄) δ 8.79 (d, J=2.9 Hz, 1H), 8.41-8.25 (m, 2H), 7.94-7.58 (m,1H), 3.75 (s, 2H), 3.60-3.06 (m, 11H), 2.65 (d, J=3.0 Hz, 3H), 1.42 (d,J=7.0 Hz, 6H), 1.36 (t, J=7.4 Hz, 3H). LCMS calc. for C₂₅H₃₂FN₈S [M+H]⁺:m/z=495.2; Found: 494.9.

Example 101.4-(3-Cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine

Step 1. 3-Cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazole

To a solution of 3-iodo-2,6-dimethylthieno[3,2-c]pyrazole (420 mg, 1.51mmol, Example 55, Step 5) in toluene (6.00 mL) and water (0.600 mL) wasadded cyclopropylboronic acid (182 mg, 2.11 mmol),dichlorobis(tricyclohexylphosphine)palladium(II) (55.7 mg, 0.076 mmol),and K₃PO₄ (1.28 g, 6.04 mmol) at room temperature. The reaction vesselwas sealed, and the mixture was degassed with N₂ (3×). The reactionmixture was heated at 100° C. overnight. The reaction mixture was cooledto room temperature and diluted with water and EtOAc. The organic layerwas separated, and the aqueous layer was extracted with EtOAc (20.0mL×2). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated. Purification by silica gelchromatography using EtOAc in heptane (10-60%) afforded the titlecompound (232 mg, 1.21 mmol, 79.9% yield) as a brown solid. LCMS calc.for C₁₀H₁₃N₂S [M+H]⁺: m/z=193.1; Found: 192.9.

Step 2.4-(3-Cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 55, Steps 8-10. Purification by prep-HPLC on a C18column (5-95%, MeCN/0.1% TFA (aq.)) afforded the TFA salt of the titlecompound as an orange solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.68 (d,J=2.9 Hz, 1H), 7.67 (dd, J=9.5, 2.8 Hz, 1H), 7.57-7.39 (m, 2H),4.56-4.43 (m, 2H), 4.40-4.21 (m, 4H), 4.18-4.05 (m, 5H), 3.27 (q, J=7.3Hz, 2H), 2.57 (d, J=3.2 Hz, 3H), 2.13 (tt, J=8.3, 5.1 Hz, 1H), 1.42-1.11(m, 5H), 0.97-0.78 (m, 2H). LCMS calc. for C₂₆H₃₀FN₈S [M+H]⁺: m/z=505.2;Found: 504.9.

Example 102.2-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol

Step 1. 3-Iodo-2,6-dimethylthieno[3,2-c]pyrazole and3-iodo-1,6-dimethyl-1H-thieno[3,2-c]pyrazole

To a solution of 3-iodo-6-methyl-1H-thieno[3,2-c]pyrazole (2.2 g, 8.33mmol, Example 55, Step 4) in THE (80 mL) at 0° C. was added potassiumtert-butoxide solution (10.0 mL, 10 mmol, 1.0 M in THF). The resultingmixture was stirred at 0° C. for 5 min. Next, iodomethane (0.62 mL, 10mmol) was added, and the reaction was stirred for 2 h. The reaction wasquenched by adding sat. aq. NH₄Cl (50 mL). The reaction mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were driedover sodium sulfate, filtered, and concentrated under reduced pressure.The crude product was purified by flash chromatography to afford amixture of the title compounds (2.2 g, 7.9 mmol, 94% yield). LCMS calc.for C₇H₈IN₂S [M+H]⁺: m/z=278.9; Found: 278.9.

Step 2: 1-(2,6-Dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one

To a mixture of 3-iodo-1,6-dimethylthieno[3,2-c]pyrazole and3-iodo-2,6-dimethylthieno[3,2-c]pyrazole (3.0 g, 10.8 mmol) in toluene(30 mL) was added tributyl(1-ethoxyvinyl)tin (5.46 mL, 16.2 mmol),followed by the addition of Pd(PPh₃)₄(1.25 g, 1.08 mmol). The mixturewas heated at 100° C. overnight. The reaction was quenched with 0.3 N KFsolution (30 mL). The mixture was stirred at room temperature for 2 h,passed through a Celite pad and extracted with EtOAc (3×30 mL). Thecombined organic phase was dried over Na₂SO₄, concentrated under reducedpressure, and redissolved in THE (20 mL). Next 1N HCl (20 mL) was added.The mixture was stirred at rt overnight. The organic phase was separatedand the aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was dried over Na₂SO₄, concentrated under reducedpressure, and purified by silica gel column chromatography (0-35%EtOAc/hexanes) to afford the title compound (735 mg, 3.78 mmol, 35.0%yield, R_(f)=0.80, 30% EtOAc/hexanes). LCMS calc. for C₉H₁₁N₂OS [M+H]⁺:m/z=195.0; Found: 195.1.

Step 3.2-(2,6-Dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol

To a solution of 1-(2,6-dimethylthieno[3,2-c]pyrazol-3-yl)ethanone (535mg, 2.75 mmol) in THE (10 mL) was added trimethyl(trifluoromethyl)silane(2.85 mL, 19.3 mmol) and TBAF solution (4.13 mL, 4.13 mmol, 1.00 M inTHF) at 0° C. The mixture was stirred for 30 min. The reaction wasquenched by adding sat. aq. NH₄Cl (10 mL). The organic phase wasseparated, and the aqueous phase was extracted with EtOAc (3×10 mL). Thecombined organic phases were dried over Na₂SO₄, concentrated, andpurified by silica gel column chromatography (0-10% EtOAc/hexanes) toafford the title compound (264 mg, 1.00 mmol, 36.3% yield). LCMS calc.for C₁₀H₁₂F₃N₂OS [M+H]⁺: m/z=265.0; Found: 265.1.

Step 4.2-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol

The title compound is synthesized by procedures analogous to thoseoutlined in Example 14, Steps 3-5. ¹H NMR (300 MHz, Methanol-d4) δ 8.77(d, J=2.8 Hz, 1H), 8.24 (dd, J=9.7, 2.9 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H),7.59 (d, J=9.6 Hz, 1H), 4.33 (s, 3H), 4.10-3.40 (m, 6H), 3.30-3.06 (m,4H), 2.63 (d, J=3.2 Hz, 3H), 1.97 (s, 3H), 1.42 (t, J=7.3 Hz, 3H). LC-MScalc. for C₂₅H₂₉F₄N₈OS [M+H]⁺: m/z=565.2; Found 565.1.

Example 103.1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one

Step 1.2,6-Dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)-2H-thieno[3,2-c]pyrazole

p-Toluenesulfonic acid monohydrate (66.1 mg, 0347 mmol) was added to amixture of 1-(2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one (135mg, 0.695 mmol, Example 102, Step 2) and ethylene glycol (0.155 mL, 2.78mmol) in toluene (3.00 mL) at room temperature. The reaction mixture washeated at 110° C. overnight. The reaction mixture was cooled to roomtemperature and purified by silica gel chromatography using EtOAc inheptane (10%) to afford the title compound (132 mg, 0.554 mmol, 79.7%yield). LC-MS calc. for C₁₁H₁₅N₂O₂S [M+H]⁺: m/z=239.1; Found 239.1.

Step 2.5-(2-Chloro-5-fluoropyrimidin-4-yl)-2,6-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)-2H-thieno[3,2-c]pyrazole

The title compound is synthesized by procedures analogous to thoseoutlined in Example 1, Steps 6-7. LC-MS calc. for C₁₅H₁₅ClFN₄O₂S [M+H]⁺:m/z=369.1; Found 368.9.

Step 3.1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one

To a solution of5-(2-chloro-5-fluoropyrimidin-4-yl)-2,6-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)-2H-thieno[3,2-c]pyrazole,TFA salt (13.3 mg, 0.0275 mmol) and5-(4-ethylpiperazin-1-yl)pyridin-2-amine (9.67 mg, 0.0469 mmol) in1,4-dioxane (1.00 mL) was added K₃PO₄ (45.9 mg, 0.216 mmol) and XPhos PdG2 (4.26 mg, 5.41 μmol, CAS 1310584-14-5). The reaction vessel wassealed, and the mixture was degassed with N₂ (3×). The reaction mixturewas heated at 100° C. for 4 h. The reaction mixture was cooled to roomtemperature and 4N aq. HCl (1.50 mL) was added. The reaction was heatedto 80° C. for 30 min. The reaction mixture was cooled to roomtemperature, filtered, and concentrated under reduced pressure. The darkresidue was purified by prep-HPLC on a C18 column (5-50% MeCN/0.1% TFA(aq.)) afforded the title compound (13.0 mg, 0.022 mmol, 62.3% yield) asa tan solid ¹H NMR (300 MHz, Methanol-d₄) δ 8.82 (d, J=2.9 Hz, 1H), 8.28(dd, J=9.7, 2.9 Hz, 1H), 7.96 (d, J=2.9 Hz, 1H), 7.64 (d, J=9.7 Hz, 1H),4.43 (s, 3H), 4.13-3.60 (m, 4H), 3.57-3.08 (m, 6H), 2.71 (d, J=3.3 Hz,3H), 2.67 (s, 3H), 1.46 (t, J=7.3 Hz, 3H). LCMS calc. for C₂₄H₂₈FN₈OS[M+H]⁺: m/z=495.2; Found: 495.4.

Example 104.1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-ol

To a solution of1-(5-(2-((5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one,TFA salt (5.80 mg, 0.012 mmol, Example 103) in MeOH (1.00 mL) was addedsodium borohydride (0.444 mg, 0.012 mmol). The reaction mixture wasstirred at room temperature for 30 min. The reaction mixture waspurified by prep-HPLC on a C18 column (2-50%, MeCN/0.1% TFA (aq.)) toafford the TFA salt of the title compound (5.00 mg, 0.008 mmol, 69.8%yield) as a brown solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.74 (s, 1H),8.20 (d, J=9.3 Hz, 1H), 7.92 (s, 1H), 7.63 (d, J=9.6 Hz, 1H), 5.22 (q,J=6.6 Hz, 1H), 4.14 (s, 3H), 4.04-2.94 (m, 10H), 2.61 (d, J=3.3 Hz, 3H),1.69 (d, J=6.5 Hz, 3H), 1.42 (t, J=7.3, 3H). LCMS calc. for C₂₄H₃₀FN₈OS[M+H]⁺: m/z=497.2; Found: 497.4.

Example 105.N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2-methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine

Step 1. 2-(2,6-Dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)propan-2-ol

The title compound is synthesized by procedures analogous to thoseoutlined in Example 17, Step 2. LCMS calc. for C₁₀H₁₅N₂OS [M-OH]⁺:m/z=211.1; Found: 211.0.

Step 2. 3-(2-methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazole

Iodomethane (0.139 mL, 2.23 mmol) and KOH (25.1 mg, 0.447 mmol) wereadded sequentially to a solution of2-(2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)propan-2-ol (47.0 mg, 0.223mmol) in DMSO (1.00 mL). The reaction mixture was stirred at roomtemperature for 2 h. The reaction was quenched with 2N aq. HCl solution(2.00 mL), and the mixture was purified by prep-HPLC on a C18 column(10-80% MeCN/0.1% TFA (aq.)) to afford the title compound (39.0 mg,0.174 mmol, 77.8% yield) as a colorless oil. LCMS calc. for C₁₁H₁₇N₂OS[M+H]⁺: m/z=225.1; Found: 224.9.

Step 3.N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2-methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 55, Steps 8-10. Purification by prep-HPLC on a C18column (2-50%, MeCN/0.1% TFA (aq.)) afforded the TFA salt of the titlecompound (5.70 mg, 0.009 mmol, 42.0% yield) as a green solid. ¹H NMR(300 MHz, Methanol-d₄) δ 8.74 (d, J=2.8 Hz, 1H), 7.69 (dd, J=9.5, 2.8Hz, 1H), 7.57-7.46 (m, 2H), 4.52 (d, J=11.2 Hz, 2H), 4.38-4.27 (m, 4H),4.26 (s, 3H), 4.20 (s, 2H), 3.30-3.25 (m, 2H), 3.17 (s, 3H), 2.62 (d,J=3.1 Hz, 3H), 1.76 (s, 6H), 1.25 (t, J=7.2 Hz, 3H). LCMS calc. forC₂₇H₃₄FN₈OS [M+H]⁺: m/z=537.2; Found: 536.9.

Example 106.4-(1,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1: 1,6-Dimethyl-3-prop-1-en-2-ylthieno[3,2-c]pyrazole and2,6-Dimethyl-3-(prop-1-en-2-yl)-2H-thieno[3,2-c]pyrazole

To a mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.91 mL, 4.85 mmol) and K₃PO₄ (2.06 g, 9.71 mmol) in 1,4-dioxane (13.5mL) and water (4.5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (237 mg,0.32 mmol), followed by the addition of a mixture of3-iodo-2,6-dimethylthieno[3,2-c]pyrazole and3-iodo-1,6-dimethyl-1H-thieno[3,2-c]pyrazole (900 mg, 3.24 mmol, Example102, Step 1). The reaction mixture was sparged with nitrogen for 5 minand stirred at 100° C. overnight. The reaction mixture was filtered, andthe filtrate was concentrated. The residue was dissolved in EtOAc (50mL) and washed with water (30 mL) and brine (30 mL). The organic layerwas dried over sodium sulfate, filtered, and concentrated. The residuewas purified by flash chromatography on a silica gel column usingEtOAc/heptanes (0-25%) to afford1,6-dimethyl-3-prop-1-en-2-ylthieno[3,2-c]pyrazole (333 mg, 1.73 mmol,54% yield) as a light yellow solid. HPLC t_(R)=6.26 min, C18-column(4.6×100 mm, 5 μm), Aq (0.1% TFA)/MeCN @ 1.0 mL/min; Gradient 5-95% B in4 min). ¹H NMR (300 MHz, CDCl₃) δ 6.95 (s, 1H), 5.35 (s, 1H), 5.23 (s,1H), 4.09 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H). LCMS calc. for C₁₀H₁₃N₂S[M+H]⁺: m/z=193.1; Found: 193.2. The same purification also afforded2,6-dimethyl-3-(prop-1-en-2-yl)-2H-thieno[3,2-c]pyrazole (180 mg, 0.94mmol, 29% yield, Example 55, Step 6) as a yellow oil. HPLC t_(R)=5.94min, C18-column (4.6×100 mm, 5 μm), Aq (0.1% TFA)/MeCN @ 1.0 mL/min,Gradient 5-95% B in 4 min).

Step 2. 1,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazole

The title compound is synthesized by procedures analogous to thoseoutlined in Example 100, Step 3. LCMS calc. for C₁₀H₁₅N₂S [M+H]⁺:m/z=195.1; Found: 195.2.

Step 3.4-(1,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 1, Steps 6-8. ¹H NMR (300 MHz, methanol-d₄) δ 8.74(d, J=2.7 Hz, 1H), 8.15 (dd, J=9.6, 2.9 Hz, 1H), 7.93 (d, J=2.8 Hz, 1H),7.69 (d, J=9.5 Hz, 1H), 4.14 (s, 3H), 4.01-3.44 (m, 6H), 3.18-3.06 (m,5H), 2.69 (d, J=3.2 Hz, 3H), 1.47-1.35 (m, 9H). LCMS calc. forC₂₅H₃₂FN₈S [M+H]⁺: 495.2; Found: 495.2.

Example 107.N-(5-Fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 52, Steps 1-8. ¹H NMR (300 MHz, methanol-d₄) δ 8.87(d, J=4.3 Hz, 1H), 8.65 (d, J=3.1 Hz, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.03(s, 1H), 7.92 (dd, J=9.2, 4.6 Hz, 1H), 4.98-4.93 (m, 1H), 2.78 (s, 3H),1.67 (d, J=6.7 Hz, 6H). LCMS calc. for C₁₇H₁₇FN₇S [M+H]⁺: m/z=370.1;Found: 369.8.

Example 108.5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-amine

Step 1. tert-Butyl 3-(6-chloropyridin-3-yl)azetidine-1-carboxylate

1,2-Dibromoethane (12.2 μL, 0.141 mmol) was added to a suspension ofzinc powder (127 mg, 1.94 mmol) in DMF (2.20 mL), and the resultingmixture was heated at 70° C. for 10 min. Upon cooling to roomtemperature, chlorotrimethylsilane (18.0 μL, 0.141 mmol) was added. Thereaction was stirred for 30 min, and then a solution of tert-butyl3-iodoazetidine-1-carboxylate (500 mg, 1.77 mmol) in DMF (2.20 mL) wasadded dropwise. The reaction was heated a 40° C. for 1 h and then2-chloro-5-iodopyridine (423 mg, 1.77 mmol),tris(dibenzylideneacetone)dipalladium(0) (12.0 mg, 35.3 μmol), andtri(2-furyl)phosphine (16.4 mg, 70.6 μmol) were added. The reactionmixture was heated at 70° C. for 18 h. The reaction mixture was cooledto room temperature and diluted with sat. NH₄Cl (aq.) (10.0 mL) andEtOAc (15.0 mL). The two layers were separated, and the aqueous layerwas extracted with EtOAc (15.0 mL×3). The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromotographyusing EtOAc/hexanes (0-100%) to afford the title compound (80.0 mg,0.298 mmol, 16.9% yield) as an orange oil. LCMS calc. forC₁₃H₁₈C₁N₂O₂[M+H]⁺: m/z=269.1; Found: 269.0.

Step 2.5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 53, Steps 3-5. LCMS calc. for C₂₃H₂₇FN₇S [M+H]⁺:m/z=452.2; Found: 452.1.

Example 109. tert-Butyl3-(2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazin-7-yl)azetidine-1-carboxylate

The title compound is synthesized by procedures analogous to thoseoutlined in Example 63. Purification via by prep-HPLC on a C18 column(25.9-53.3%, MeCN/0.1% TFA (aq.)) afforded the title compound as the TFAsalt, a white solid. LCMS calc. for C₃₁H₃₇FN₉O₃S [M+H]⁺: m/z=634.3;Found: 634.0.

Example 110.2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one

The title compound is synthesized by procedures analogous to thoseoutlined in Example 63. Purification via by prep-HPLC on a C18 column(17.2-37.2%, MeCN/0.1% TFA (aq.)) afforded the title compound as the TFAsalt, a white solid. LCMS calc. for C₂₇H₂₈F₂N₇OS [M+H]⁺: m/z=536.2;Found: 536.0.

Example 111.5-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine

Step 1. 3-Isopropyl-6-methyl-1,3-dihydro-2H-thieno[2,3-d]imidazol-2-one

Diphenyl phosphoryl azide (1.78 g, 6.45 mmol) was added dropwise to amixture of 4-methyl-2-(propan-2-ylamino)thiophene-3-carboxylic acid(1.03 g, 5.16 mmol, Example 52 Step 2) and triethylamine (1.80 mL, 13.0mmol) in toluene (15.0 mL) at room temperature. The reaction mixture wasstirred for 1 h. The reaction mixture washed with sat. NaHCO₃ (aq.)(15.0 mL) and water (15.0 mL), dried over MgSO₄, and filtered. Thefiltrate was heated at 100° C. for 18 h. The reaction mixture was cooledto room temperature and partitioned between sat. NaHCO₃ (aq.) (30.0 mL)and EtOAc (30.0 mL). The organic layer was separated, and the aqueouslayer was extracted with EtOAc (15.0 mL×3). The combined organic layerswere washed with sat. NaHCO₃ (aq.) (15.0 mL), water (15.0 mL), and brine(15.0 mL). The organic layer was then dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-50% EtOAc/heptanes) to give the title compound(600 mg, 3.10 mmol, 59.0% yield) as brown solid. LCMS calc. forC₉H₁₃N₂OS [M+H]⁺: m/z=197.1; Found: 197.1.

Step 2. 2-Chloro-3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazole

A mixture of3-isopropyl-6-methyl-1,3-dihydro-2H-thieno[2,3-d]imidazol-2-one (1.24 g,6.30 mmol) and phosphorous oxychloride (5.80 g, 37.8 mmol) was stirredat 100° C. for 24 h. The reaction mixture was cooled to room temperatureand poured into ice-cold sat. NaHCO₃ (aq.) with vigorous stirring. Themixture was extracted with EtOAc (20.0 mL×3), and the combined organicextracts were washed with brine (20.0 mL), dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude residue was purifiedby silica gel chromatography (0-50% EtOAc/heptanes) to give the titlecompound (707 mg, 3.29 mmol, 52.2% yield) as colorless oil. LCMS calc.for C₉H₁₂ClN₂S [M+H]⁺: m/z=215.0; Found: 215.0.

Step 3. 3-Isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine

A mixture of 2-chloro-3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazole(521 mg, 2.43 mmol) and dimethylamine (5.00 mL, 40% in water) was heatedat 140° C. in a sealed tube for 2 d. Upon cooling to room temperature,the reaction mixture was concentrated. The residue was purified viasilica gel chromatography (0-50% EtOAc/heptanes) to afford the titlecompound (74.0 mg, 0.330 mmol, 14.0% yield) as colorless oil. LCMS calc.for C₁₁H₁₈N₃S [M+H]⁺: m/z=224.1; Found: 224.1.

Step 4.5-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine

The title compound is synthesized by procedures analogous to thoseoutlined in Example 1, Steps 6-8. Purification via by prep-HPLC on a C18column (6-80%, MeCN/0.1% TFA (aq.)) afforded the title compound as theTFA salt, a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ 8.66 (d, J=3.4 Hz,1H), 7.67 (dd, J=9.5, 2.8 Hz, 1H), 7.53-7.46 (m, 2H), 5.03-4.97 (m, 1H),4.56-4.14 (m, 8H), 3.28-3.23 (m, 2H), 3.18 (s, 6H), 2.73 (d, J=2.8 Hz,3H), 1.62 (d, J=6.7 Hz, 6H), 1.22 (t, J=7.2 Hz, 3H). LCMS calc. forC₂₇H₃₅FN₉S [M+H]⁺: m/z=536.3; Found: 536.0.

Example 112.N-(5-(2-Ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

Step 1. tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

A vial was charged with tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.55 g, 12.0 mmol),imidazole (2.44 g, 35.9 mmol), triphenylphosphine (6.27 g, 23.9 mmol),and iodine (4.55 g, 17.9 mmol), toluene (40 mL) was added. The mixturewas refluxed for 1 h. The mixture was cooled to room temperature, washedwith H₂O (40 mL), dried over Na₂SO₄, filtered, and concentrated to givea colorless solid. The crude residue was purified by silica gelchromatography (0-20% EtOAc/heptanes) to afford the title compound (3.55g, 10.9 mmol, 91.8% yield) as a colorless solid. R_(f)=0.7 (20%EtOAc/hexane).

Step 2. tert-Butyl6-(6-aminopyridin-3-yl)-2-azaspiro[3.3]heptane-2-carboxylate

A vial was charged with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (82.1 mg,0.373 mmol), tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate(120.5 mg, 0.3729 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.3 mg,0.0373 mmol) and K₃PO₄ (237.4 mg, 1.119 mmol), 1,4-dioxane (3 mL), andwater (1 mL) were added. The mixture was heated at 100° C. overnight.The mixture was concentrated and partitioned in DCM (10 mL) and water(10 mL). The biphasic mixture was then filtered via a syringe filter.The organic layer was separated, and the aqueous phase was extractedwith DCM (10 mL×3). The combined organic phase was dried over Na₂SO₄,filtered, concentrated, and purified by silica gel chromatography (0-10%MeOH/DCM) to afford the title compound (40.1 mg, 0.138 mmol, 37.0%yield). LCMS calc. for C₁₆H₂₄N₃O₂ [M+H]⁺: m/z=290.2; Found: 290.0.

Step 3.N-(5-(2-Azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 1, Step 8 to afford the title compound as a TFA salt. LCMS calc.for C₂₄H₂₇FN₇S [M+H]⁺: m/z=464.2; Found: 464.0.

Step 4.N-[5-(2-Ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

To a suspension ofN-[5-(2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine,TFA salt (41.6 mg, 0.0720 mmol) in methanol (5 mL) was addedacetaldehyde (56.9 μL, 0.449 mmol, 40 wt. % in H₂O), acetic acid (18 μL,0.31 mmol) and NaBH₃CN (56.4 mg, 0.0897 mmol). The suspension wasstirred at room temperature for 30 min. To the mixture was added MeCN (2mL) and H₂O (1 mL). The mixture was filtered and purified by prep-HPLCon a C18 column (2-40% MeCN/0.1% TFA (aq.)) to afford the title compoundas a TFA salt (24.3 mg, 0.0401 mmol, 55.7% yield), a yellow solid. ¹HNMR (300 MHz, methanol-d4) δ 8.74 (d, J=3.2 Hz, 1H), 8.29 (dd, J=9.1,2.1 Hz, 1H), 8.22-8.11 (m, 2H), 7.59 (d, J=9.1 Hz, 1H), 5.03-4.94 (m,1H), 4.46 (dd, J=10.8, 2.6 Hz, 1H), 4.29-4.14 (m, 2H), 4.03 (d, J=10.9Hz, 1H), 3.68-3.56 (m, 1H), 3.23 (q, J=7.2 Hz, 2H), 2.92-2.78 (m, 4H),2.76-2.65 (m, 1H), 2.61-2.40 (m, 2H), 1.68 (d, J=6.7 Hz, 6H), 1.21 (t,J=7.2 Hz, 3H). LCMS calc. for C₂₆H₃₁FN₇S [M+H]⁺: m/z=492.2; Found 492.0.

Example 113.4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1. tert-Butyl N-[6-(4-ethylpiperazin-1-yl)pyridin-2-yl]carbamate

tert-Butyl N-(6-bromopyridin-2-yl)carbamate (600.0 mg, 2.197 mmol) wasstirred in 1-ethylpiperazine (5.8 mL, 44 mmol) at 90° C. overnight. Thereaction mixture was diluted with DCM and poured into saturated NaHCO₃(aq.) (10 mL). After extraction with DCM (10 mL×3), the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by silica gel chromatography (10%-80% EtOAc/heptanes) toafford the title compound (588 mg, 1.92 mmol, 87.4% yield). LCMS calc.for C₁₆H₂₇N₄O₂ [M+H]⁺: 307.2; Found: 307.1

Step 2. 6-(4-Ethylpiperazin-1-yl)pyridin-2-amine

A solution of tert-butylN-[6-(4-ethylpiperazin-1-yl)pyridin-2-yl]carbamate (588.0 mg, 1.919mmol) in DCM (6 mL) was added TFA (26.1 mmol, 2 mL) at 0° C. Thereaction was slowly warmed to room temperature and stirred for 6 h. Thesolvent was removed under vacuum. The residue was redissolved in 10:1DCM/MeOH (20 mL). NaHCO₃ (100 mg) was added, and the mixture was stirredfor 15 min and then filtered. The filtrate was concentrated and purifiedby silica gel chromatography (0-10% MeOH/DCM) to afford the titlecompound (362 mg, 1.75 mmol, 91.4% yield). LCMS calc. forC₁₁H₁₉N₄[M+H]⁺: m/z=207.2; Found 207.1.

Step 3.4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 1, Step 8 to afford the title compound as a TFA salt, a lightyellow solid. ¹H NMR (300 MHz, CD₃OD) δ 8.60 (d, J=2.9 Hz, 1H),7.76-7.60 (m, 2H), 6.64-6.52 (m, 1H), 4.97-4.80 (m, 1H), 3.81-3.45 (m,2H), 3.29-3.13 (m, 8H), 2.85 (s, 3H), 2.62 (d, J=3.8 Hz, 3H), 1.68 (d,J=6.7 Hz, 6H), 1.40 (t, J=7.3 Hz, 3H). LCMS calc. for C₂₅H₃₁FN₈S [M+H]⁺:m/z=495.2; Found 495.1.

Example 114.5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]pyrimidin-2-amine

Step 1. 5-(1-Methylpyrrolidin-3-yl)oxy-2-nitropyridine

To a solution of 1-methylpyrrolidin-3-ol (391.5 mg, 3.870 mmol) inN,N-dimethylacetamide (10 mL) at 0° C. was added potassium tert-butoxide(4.2 mL, 4.2 mmol, 1.0 M in THF) portion-wise and then5-fluoro-2-nitropyridine (500.0 mg, 3.519 mmol) portion-wise. Theresulting dark solution was stirred at 0° C. for 30 min and allowed towarm to room temperature, stirring for 18 h. The reaction mixture wasquenched with water (20 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layers were washed with water (10 mL) and brine (10mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (0-75% MeOH/MTBE) to afford thetitle compound (693 mg, 3.10 mmol, 88.3% yield) as a yellow solid.R_(f)=0.3 (30% MeOH/MTBE).

Step 2. 5-(1-Methylpyrrolidin-3-yl)oxypyridin-2-amine

To a stirred solution of 5-(1-methylpyrrolidin-3-yl)oxy-2-nitropyridine(580.0 mg, 2.598 mmol) in methanol (30 mL) was added palladium on carbon(27.7 mg, 0.260 mmol, 10 wt %), and the reaction vessel was charged withH₂. The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated. The residue was purified by silica gel chromatography(5-30% MeOH/DCM) to afford the title compound (390 mg, 2.02 mmol, 77.7%yield). LCMS calc. for C₁₀H₁₆N₃O [M+H]⁺: m/z=194.1; Found 194.0.

Step 3.5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 1, Step 8 to afford the title compound as a TFA salt. ¹H NMR(300 MHz, methanol-d₄) δ 8.67 (dd, J=3.3, 1.9 Hz, 1H), 8.10 (d, J=1.2Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.97-7.88 (m, 1H), 7.83 (d, J=9.5 Hz,1H), 5.32 (s, 1H), 5.00-4.95 (m, 1H), 4.08-3.49 (m, 4H), 3.06 (s, 3H),2.84 (d, J=1.8 Hz, 3H), 2.36 (t, J=7.3 Hz, 2H), 1.69 (d, J=6.7 Hz, 6H).LCMS calc. for C₂₃H₂₇FN₇OS [M+H]⁺: m/z=468.2; Found 467.9.

Example 115.5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylmorpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine

Step 1. 5-(1-Ethoxyethenyl)-2-nitropyridine

To a solution of tributyl(1-ethoxyvinyl)tin (2.08 mL, 6.17 mmol) and5-bromo-2-nitropyridine (1.14 g, 5.61 mmol) in toluene (30 mL) was addedtetrakis(triphenylphosphine) palladium(0) (454 mg, 0.392 mmol). Themixture was heated at 100° C. for 6 h. KF was added (2 g, 30 mmol), andthe mixture was stirred at room temperature for 1 h. H₂O (30 mL) andEtOAc (50 mL) were added. The mixture was passed through a Celite pad.The organic layer was separated, and the aqueous phase was extractedwith EtOAc (30 mL×3). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel chromatography (0%-10%, EtOAc/hexanes) to give the title compound(1.08 g, 5.56 mmol, 99.2% yield) as a yellow oil. LCMS calc. forC₉H₁₁N₂O₃ [M+H]⁺: m/z=195.1; Found: 195.0.

Step 2. 2-Bromo-1-(6-nitropyridin-3-yl)ethanone

To a solution of 5-(1-ethoxyethenyl)-2-nitropyridine (1.08 g, 5.56 mmol)in THE (15 mL) and water (6 mL) was added N-bromosuccinimide (0.99 g,5.6 mmol). The mixture was stirred for 2 h at room temperature. To themixture was added hexanes (10 mL) and EtOAc (10 mL). The organic layerwas separated, and the aqueous layer was extracted with EtOAc (10 mL×3).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was triturated with MTBE to give the titlecompound (1.11 g, 4.53 mmol, 81.4% yield) as a beige solid. LCMS calc.for C₇H₄BrN₂O₃[M−H]⁻: m/z=242.9; Found: 242.8.

Step 3. 2-Nitro-5-(oxiran-2-yl)pyridine

To a solution of 2-bromo-1-(6-nitropyridin-3-yl)ethanone (55.0 mg, 0.224mmol) in methanol (5 mL) was added sodium borohydride (8.5 mg, 0.22mmol). The mixture was stirred for 2 h at room temperature. The mixturewas diluted with water and purified by prep-HPLC on a C18 column (5%-60%MeCN/0.1% TFA(aq.)) to give the title compound (5.0 mg, 0.030 mmol, 13%yield) as a beige solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d, J=2.3 Hz,1H), 8.36-8.25 (m, 1H), 8.09 (dd, J=8.4, 2.2 Hz, 1H), 4.23 (dd, J=4.3,2.5 Hz, 1H), 3.28 (dd, J=5.3, 4.2 Hz, 1H), 3.04 (dd, J=5.3, 2.6 Hz, 1H).

Step 4.2-((2-Hydroxyethyl)(methyl)amino)-1-(6-nitropyridin-3-yl)ethan-1-ol

To a solution of 2-nitro-5-(oxiran-2-yl)pyridine (61.3 mg, 0.369 mmol)in DMF (1 mL) was added 2-(methylamino)ethanol (122.6 μL, 1.526 mmol).The mixture was heated at 80° C. for 6 h. The mixture was purified byprep-HPLC on a C18 column (0%-20% MeCN/0.1% TFA(aq.)) to give the titlecompound as a TFA salt (52.0 mg, 0.146 mmol, 39.7% yield), a colorlessoil. LCMS calc. for C₁₀H₁₆N₃O₄ [M+H]⁺: m/z=242.1; Found: 241.9.

Step 5. 1-(6-Aminopyridin-3-yl)-2-[2-hydroxyethyl(methyl)amino]ethanol

To a solution of2-[2-hydroxyethyl(methyl)amino]-1-(6-nitropyridin-3-yl)ethanol, TFA salt(47.0 mg, 0.132 mmol, from Step 4) in methanol (4 mL) was addedpalladium on carbon (10 mg, 10 wt %). The mixture was stirred under anatmosphere of H₂ overnight. The mixture was filtered through a syringefilter and concentrated to afford the title compound, which was usedwithout any further purification. LCMS calc. for C₁₀H₁₈N₃O₂ [M+H]⁺:m/z=212.1; Found: 212.0.

Step 6. 5-(4-Methylmorpholin-2-yl)pyridin-2-amine

A mixture of1-(6-aminopyridin-3-yl)-2-[2-hydroxyethyl(methyl)amino]ethanol (fromStep 5) and conc. H₂SO₄ (1.0 mL, 18.37 mmol) was stirred for 1 h at roomtemperature. The mixture was cooled to 0° C., and water (3 mL) and DCM(3 mL) were added sequentially. NH₄OH (10 mL) was then added slowly. Theorganic layer was separated, and the aqueous layer was extracted withDCM (10 mL×3). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated to afford the title compound (15.1 mg, 0.0781mmol, 59.2% yield over two steps) as a colorless oil. LCMS calc. forC₁₀H₁₆N₃O [M+H]⁺: m/z=194.1; Found: 194.0.

Step 7.5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylmorpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 1, Step 8 to afford the title compound as a TFA salt. ¹H NMR(300 MHz, CD₃OD) δ 8.75 (d, J=3.0 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.21(dd, J=9.1, 2.2 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 5.02-4.90 (m, 2H), 4.34(dd, J=13.3, 3.7 Hz, 1H), 4.05 (t, J=12.7 Hz, 1H), 3.78 (d, J=12.5 Hz,1H), 3.64-3.51 (m, 1H), 3.23-3.14 (m, 2H), 3.01 (s, 3H), 2.85 (s, 3H),2.72 (d, J=3.2 Hz, 3H), 1.68 (d, J=6.7 Hz, 6H). LCMS calc. forC₂₄H₂₉FN₇OS [M+H]⁺: m/z=482.2; Found 481.8.

Example 116.N-[5-[1-(4-Ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

Step 1. 1-(6-Chloropyridin-3-yl)ethanol

To methylmagnesium chloride (2.35 mL, 7.1 mmol, 3.0 M in THF) was addeda solution of 2-chloro-5-formylpyridine (500.0 mg, 3.531 mmol) in THE (6mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h.The reaction was quenched with sat. NH₄Cl (aq.) (5 mL) and extractedwith EtOAc (5 mL×3). The combined organic layers were washed with brine(10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (0-40%, EtOAc/heptanes) to affordthe title compound (495.1 mg, 3.141 mmol, 88.97% yield). LCMS calc. forC₇H₉ClNO [M+H]⁺: m/z=158.0, 160.0; Found: 157.6, 159.8.

Step 2. 1-(6-Chloropyridin-3-yl)ethyl methanesulfonate

To a solution of 1-(6-chloropyridin-3-yl)ethanol (450.0 mg, 2.855 mmol)and triethylamine (1.19 mL, 8.57 mmol) in DCM (10 mL) was addedmethanesulfonyl chloride (0.33 mL, 4.9 mmol) dropwise at 0° C. Thereaction mixture was then stirred at room temperature for 2 h. Thereaction was diluted with DCM (10 mL), washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, filtered, and concentrated to affordthe title compound (606.1 mg), which was used without furtherpurification. LCMS calc. for C₈H₁₁ClNO₃S [M+H]+: m/z=236.0, 238.0;Found: 235.8, 237.8.

Step 3. tert-Butyl4-[1-(6-chloropyridin-3-yl)ethyl]piperazine-1-carboxylate

To a solution of 1-(6-chloropyridin-3-yl)ethyl methanesulfonate (600.0mg, from Step 2) and tert-butyl 1-piperazinecarboxylate (948.3 mg, 5.091mmol) in DMF (6 mL) was added triethylamine (1.77 mL, 12.7 mmol). Thereaction mixture was stirred at 50° C. for 1 h. The reaction was dilutedwith water (10 mL) and extracted with EtOAc (10 mL×3). The combinedorganic layers were washed with water (10 mL) and brine (10 mL), driedover Na₂SO₄, filtered, and concentrated. The residue was purified bysilica gel chromatography (5-90%, EtOAc/heptanes) to afford the titlecompound (733.2 mg, 2.250 mmol). LCMS calc. for C₁₆H₂₅ClN₃O₂[M+H]⁺:m/z=326.2, 328.2; Found: 326.0, 327.8.

Step 4. 1-[1-(6-Chloropyridin-3-yl)ethyl]piperazine

To a solution of tert-butyl4-[1-(6-chloropyridin-3-yl)ethyl]piperazine-1-carboxylate (733.2 mg,2.250 mmol) in DCM (1 mL) was added TFA (1.0 mL, 13 mmol). The reactionmixture was stirred at room temperature for 2 h. The mixture wasconcentrated to afford the title compound (505.3 mg), which was usedwithout further purification. LCMS calc. for C₁₁H₁₇ClN₃ [M+H]⁺:m/z=226.1, 228.1; Found: 225.9, 227.9.

Step 5. 1-[1-(6-Chloropyridin-3-yl)ethyl]-4-ethylpiperazine

To a solution of 1-[1-(6-chloropyridin-3-yl)ethyl]piperazine (490.0 mg,from Step 4) in methanol (10 mL) was added acetic acid (0.01 mL, 0.2mmol) and acetaldehyde (1.38 mL, 10.9 mmol, 40 wt % in H₂O). Thereaction mixture was stirred at room temperature for 10 min, and thensodium cyanoborohydride (409.3 mg, 6.513 mmol) was added. The resultingmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure. The residue was dissolved in EtOAc (10mL), washed with sat. NaHCO₃ (aq.) (10 mL) and brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (5-100%, EtOAc/heptanes) to afford the title compound(180.2 mg, 0.7100 mmol). LCMS calc. for C₁₃H₂₁ClN₃ [M+H]⁺: m/z=254.1,256.1; Found: 254.0, 255.9.

Step 6.5-(2-Chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazole

The title compound was synthesized to procedures analogous to Example52, Steps 1-7. ¹H NMR (300 MHz, CDCl₃) δ 8.55 (d, J=2.5 Hz, 1H), 8.11(d, J=0.9 Hz, 1H), 4.75 (dq, J=13.3, 6.7 Hz, 1H), 2.90 (s, 3H), 1.71 (d,J=6.7 Hz, 6H). LCMS calc. for C₁₃H₁₃ClFN₄S [M+H]⁺: m/z=311.1; Found:311.1.

Step 7.N-[5-[1-(4-Ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

The title compound was synthesized to procedures analogous to Example53, Steps 1 and 5 to yield the title compound as a TFA salt. ¹H NMR (300MHz, CD₃OD) δ 8.75 (d, J=3.2 Hz, 1H), 8.37 (dd, J=9.1, 2.0 Hz, 1H), 8.33(s, 1H), 8.14 (d, J=0.9 Hz, 1H), 7.67 (d, J=9.0 Hz, 1H), 4.99-4.92 (m,1H), 3.85 (t, J=6.7 Hz, 1H), 3.70-3.34 (m, 3H), 3.29-3.00 (m, 7H), 2.82(s, 3H), 1.69 (d, J=6.7 Hz, 6H), 1.48 (d, J=6.7 Hz, 3H), 1.35 (t, J=7.3Hz, 3H). LCMS calc. for C₂₆H₃₄FN₈S [M+H]⁺: m/z=509.3; Found: 509.3.

Example 117.3-[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one

Step 1. Methyl 2-bromo-2-(6-chloropyridin-3-yl)acetate

To a solution of methyl 2-(6-chloropyridin-3-yl)acetate (510.0 mg, 2.748mmol) in acetonitrile (5 mL) was added N-bromosuccinimide (580.2 mg,3.260 mmol) and 2,2′-azobisisobutyronitrile (45.1 mg, 0.275 mmol). Thereaction mixture was stirred at room temperature for 5 h. The mixturewas concentrated under reduced pressure and purified by silica gelchromatography (0-50%, EtOAc/heptanes) to afford the title compound(490.1 mg, 1.853 mmol, 67.43% yield). LCMS calc. for C₈H₈BrClNO₂ [M+H]⁺:m/z=263.9, 265.9; Found: 264.0, 265.9.

Step 2. 3-(6-Chloropyridin-3-yl)-1,4-dimethylpiperazin-2-one

To a solution of methyl 2-bromo-2-(6-chloropyridin-3-yl)acetate (490.1mg, 1.853 mmol) in ethanol (10 mL) was addedN,N′-dimethylethylenediamine (0.24 mL, 2.2 mmol). After stirring at roomtemperature overnight, the reaction mixture was concentrated.Purification via silica gel chromatography (5-100%, EtOAc/heptanes)afforded the title compound (250.5 mg, 1.045 mmol, 56.40% yield). LCMScalc. for C₁₁H₁₅ClN₃O [M+H]⁺: m/z=240.0, 242.0; Found: 239.9, 242.0.

Step 3.3-[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one

The title compound was synthesized to procedures analogous to Example53, Step 5 to afford the title compound as a TFA salt. ¹H NMR (300 MHz,CD₃OD) δ 8.76 (d, J=3.1 Hz, 1H), 8.42 (d, J=2.2 Hz, 1H), 8.29 (dd,J=9.1, 2.2 Hz, 1H), 8.14 (s, 1H), 7.72 (d, J=9.0 Hz, 1H), 5.07-4.97 (m,1H), 4.36 (s, 1H), 3.91-3.79 (m, 1H), 3.47 (dt, J=12.4, 3.2 Hz, 1H),3.40-3.33 (m, 1H), 3.09 (dd, J=11.6, 3.9 Hz, 1H), 3.04 (s, 3H), 2.88 (s,3H), 2.47 (s, 3H), 1.71 (d, J=6.6 Hz, 6H). LCMS calc. for C₂₄H₂₈FN₈OS[M+H]⁺: m/z=495.2; Found: 494.9.

Example 118.((8aS)-6-(6-((5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one(single diastereomer)

Step 1. Ethyl(2S)-5-(6-Chloropyridin-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoate

To a solution of 2-chloro-5-iodopyridine (10 g, 42 mmol) in THE (50 mL)was added isopropyl magnesium chloride (19 mL, 38 mmol, 2.0 M in THF)dropwise at −60° C. The reaction mixture was warmed slowly to 0° C. over30 min and then stirred for 1 h at 0° C. The reaction mixture was cooledto −20° C., and 1-O-tert-butyl 2-O-ethyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (8.6 g, 33 mmol) in THE (15 mL)was added. The reaction mixture was slowly warmed to room temperatureover 30 min and stirred for 1 h. The reaction was quenched with 2 M HCl(20 mL) and stirred for 30 min. The organic layer was separated, and theaqueous layer was extracted with DCM (20 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified by silica gel chromatography (5%-35%, EtOAc/heptanes) toafford the title compound (11 g, 29 mmol, 89% yield). ¹H NMR (300 MHz,CDCl₃) δ 8.93 (d, J=2.28 Hz, 1H), 8.23-8.15 (m, 1H), 7.45 (d, J=8.35 Hz,1H), 5.15 (bs, 1H), 4.43-4.30 (m, 1H), 4.28-4.18 (m, 2H), 3.20-2.97 (m,2H), 2.44-2.31 (m, 1H), 2.14-2.00 (m, 1H), 1.42 (s, 9H), 1.33-1.27 (m,3H). LCMS calc. for C₁₇H₂₄ClN₂O₅[M+H]⁺: m/z=371.1; Found: 370.9.

Step 2. Ethyl(2S)-5-(6-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate

To a solution of ethyl(2S)-5-(6-chloropyridin-3-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoate(11 g, 29 mmol) in DCM (30 mL) was added TFA (9 mL). The reactionmixture was stirred at room temperature overnight. The reaction mixturewas concentrated, dissolved in EtOAc (100 mL), and washed subsequentlywith sat. K₂CO₃ (aq.) (30 mL×2) and sat. NH₄Cl (aq.) (30 mL). Theorganic layer was dried over Na₂SO₄, filtered, and concentrated toafford the title compound (7.2 g), which was used without furtherpurification. LCMS for calc. for C₁₂H₁₄ClN₂O₂[M+H]⁺: m/z=253.1; found253.0.

Step 3. [(2S)-5-(6-Chloropyridin-3-yl)pyrrolidin-2-yl]methanol

To a solution of ethyl(2S)-5-(6-chloropyridin-3-yl)-3,4-dihydro-2H-pyrrole-2-carboxylate (7.2g, from Step 2) in ethanol (200 mL) was added sodium borohydride (5.29g, 140 mmol) in three portions over 30 min. The reaction mixture wasstirred overnight at room temperature. The reaction mixture wasconcentrated, redissolved in DCM (100 mL), and filtered through Celite.The mixture was washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, filtered, and concentrated. The residue was purified bychromatography (5%-30% EtOAc/heptanes with 10% MeOH) to afford the titlecompound (3.7 g, 18 mmol, 62% yield over two steps). ¹H NMR (300 MHz,CDCl₃) δ 8.39 (dd, J=2.47, 0.57 Hz, 1H), 7.80-7.66 (m, 1H), 7.37-7.25(m, 1H), 4.38-4.24 (m, 1H), 3.74-3.40 (m, 3H), 2.43 (bs, 2H), 2.38-2.16(m, 1H), 2.12-1.93 (m, 1H), 1.85-1.57 (m, 2H). LCMS for calc. forC₁₀H₁₄ClN₂O [M+H]⁺: m/z=213.1; found 213.0.

Step 4. Ethyl2-[(5S)-2-(6-Chloropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl]acetate(Single Diastereomer)

To a solution of [(2S)-5-(6-chloropyridin-3-yl)pyrrolidin-2-yl]methanol(460.0 mg, 2.163 mmol) and ethyl 2-oxoacetate (0.43 mL, 4.3 mmol) in DCM(10 mL) was added sodium triacetoxyborohydride (900.0 mg, 4.247 mmol).The reaction mixture was stirred at room temperature overnight. Thereaction was quenched with sat. NaHCO₃ (aq.) (10 mL). The organic layerwas separated, and the aqueous layer was extracted with DCM (20 mL×3).The combined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered, and concentrated. The residue was purified bychromatography (5%-20% EtOAc/heptanes with 10% MeOH) to afford the titlecompound (397.1 mg, 1.329 mmol, 61.44% yield), the major diastereomer.Major diastereomer: R_(f)=0.15 (1:2 EtOAc/heptane with 10% MeOH). Minordiastereomer: R_(f)=0.25 (1:2 EtOAc/heptane with 10% MeOH). LCMS calc.for C₁₄H₂₀ClN₂O₃[M+H]⁺: m/z⁼299.1; found 299.2.

Step 5. Ethyl2-((2S)-2-(azidomethyl)-5-(6-chloropyridin-3-yl)pyrrolidin-1-yl)acetate(Single Diastereomer)

To a solution of ethyl2-[(5S)-2-(6-chloropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl]acetate(370.1 mg, 1.239 mmol, from Step 4) and triphenylphosphine (487.0 mg,1.857 mmol) in THE (10 mL) at 0° C. was added diisopropylazodicarboxylate (366 μL, 1.86 mmol). The reaction mixture was stirredat room temperature for 30 min, and then diphenyl phosphoryl azide (400μL, 1.86 mmol]) was added dropwise. The reaction mixture was stirredovernight. The reaction was quenched with sat. NaHCO₃ (aq.) (20 mL). Theorganic layer was separated, and the aqueous layer was extracted withDCM (25 mL×3). The combined organic layers were washed with brine (25mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (5-20%, EtOAc/heptanes) to affordthe title compound (200.0 mg, 0.6177 mmol, 49.85% yield). LCMS calc. forC₁₄H₁₉ClN₅O₂[M+H]⁺: m/z=324.1; found 323.9.

Step 6.(8aS)-6-(6-Chloropyridin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-3(4H)-one(Single Diastereomer)

To a solution of ethyl2-[(2S)-2-(azidomethyl)-5-(6-chloropyridin-3-yl)pyrrolidin-1-yl]acetate(190.0 mg, 0.5868 mmol, from Step 5) in THE (5 mL) and water (0.5 mL)was added triphenylphosphine (185.1 mg, 0.7057 mmol). The reactionmixture was stirred at 60° C. overnight. The reaction mixture wasconcentrated and purified by prep-HPLC on a C18 column (10-60%,MeCN/0.1% TFA (aq.)) to afford the title compound as a TFA salt (113.1mg, 0.3092 mmol, 52.69% yield). ¹H NMR (300 MHz, CD₃OD) δ 8.42 (d,J=2.47 Hz, 1H), 7.93 (dd, J=8.35, 2.47 Hz, 1H), 7.52 (d, J=8.35 Hz, 1H),3.85 (t, J=8.64 Hz, 1H), 3.59 (dd, J=12.05, 3.89 Hz, 1H), 3.41-3.33 (m,1H), 3.29-3.18 (m, 2H), 3.17-3.08 (m, 1H), 2.57-2.43 (m, 1H), 2.31-2.19(m, 1H), 2.08-1.95 (m, 1H), 1.90-1.76 (m, 1H). LCMS calc. forC₁₂H₁₅ClN₃O [M+H⁺]: m/z=252.1, found 252.0.

Step 7.(8aS)-6-(6-Chloropyridin-3-yl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one(Single Diastereomer)

To a solution of(8aS)-6-(6-Chloropyridin-3-yl)hexahydropyrrolo[1,2-a]pyrazin-3(4H)-one,TFA salt (70.0 mg, 0.191 mmol, from Step 6) in DMF (2 mL) was addedsodium hydride (24.5 mg, 0.612 mmol, 60% wt in mineral oil). Thereaction mixture was stirred at room temperature for 30 min. Then methyliodide (26 μL, 0.41 mmol) was added. The reaction mixture was stirred atroom temperature for 1 h. The reaction was quenched with water (5 mL),and the reaction mixture was extracted with EtOAc (5 mL×3). The combinedorganic layers were washed with brine (4 mL×3), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (25-40%, EtOAc/heptanes with 0.5% MeOH) to afford thetitle compound (52.2 mg, 0.196 mmol, 97.4% yield). ¹H NMR (300 MHz,CDCl₃) δ 8.24 (d, J=2.28 Hz, 1H), 7.61 (dd, J=8.35, 2.47 Hz, 1H),7.27-7.20 (m, 1H), 3.35-3.22 (m, 4H), 2.92 (s, 3H), 2.80-2.63 (m, 2H),2.32-2.20 (m, 1H), 2.04-1.95 (m, 1H), 1.72-1.58 (m, 2H). LCMS calc. forC₁₃H₁₇ClN₃O [M+H]⁺: m/z=266.1, found 266.1.

Step 8.(8aS)-6-[6-[[4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino]pyridin-3-yl]-2-methyl-1,4,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-3-one(Single Diastereomer)

The title compound was synthesized to procedures analogous to Example53, Step 5 to afford the title compound as a TFA salt. ¹H NMR (300 MHz,CD₃OD) δ 8.79 (d, J=3.23 Hz, 1H), 8.35 (dd, J=9.11, 2.09 Hz, 1H), 8.30(d, J=1.71 Hz, 1H), 7.63 (d, J=8.92 Hz, 1H), 5.04-4.90 (m, 1H),3.63-3.49 (m, 2H), 3.42-3.33 (m, 2H), 3.01-2.94 (m, 4H), 2.86 (s, 4H),2.73 (d, J=3.04 Hz, 3H), 2.51-2.38 (m, 1H), 2.21-2.07 (m, 1H), 1.90-1.72(m, 2H), 1.67 (d, J=6.64 Hz, 6H). LCMS calc. for C₂₇H₃₂FN₈OS [M+H]⁺:m/z=535.2, found 535.2.

Example 119.4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

Step 1. 1-(2-Bromopyridin-4-yl)-4-ethylpiperazine

To a solution of tert-butyl4-(2-bromopyridin-4-yl)piperazine-1-carboxylate (250 mg, 0.730 mmol) inDCM (5 mL) was added TFA (2.5 mL) at 0° C. The reaction was stirred atroom temperature for 2 h. The reaction mixture was concentrated anddried in vacuum. The residue was dissolved in methanol (10 mL), andacetaldehyde (96.5 mg, 2.19 mmol) and sodium cyanoborohydride (413 mg,6.57 mmol) were added. The reaction was stirred at room temperature for2 h. The reaction was quenched with sat. NaHCO₃ (aq.) (10 mL) andextracted with DCM (10 mL×3). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. The residue was purified bysilica gel chromatography (0-10%, MeOH/DCM) to give the title compound(152 mg, 0.563 mmol, 77.1% yield). LCMS calc. for C₁₁H₁₇BrN₃ [M+H]⁺:270.1, 272.1; Found: 270.1, 272.0.

Step 2.4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 53, Step 5. ¹H NMR (300 MHz, CD₃OD) δ 8.74 (d, J=2.9Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.04 (dd, J=7.6, 2.7 Hz, 1H), 6.78 (d,J=2.6 Hz, 1H), 5.04-4.99 (m, 1H), 4.25-3.41 (m, 8H), 3.30 (m, 2H), 2.89(s, 3H), 2.73 (d, J=3.1 Hz, 3H), 1.68 (d, J=6.7 Hz, 6H), 1.42 (t, J=7.3Hz, 3H). LCMS calc. for C₂₅H₃₂FN₈S [M+H]⁺: m/z=495.2; Found 495.1.

Example 120.4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 52 to afford the title compound as its TFA salt. ¹HNMR (300 MHz, CD₃OD) δ 9.08 (s, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.34 (dd,J=9.1, 2.2 Hz, 1H), 8.05 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 5.01 (q, J=6.8Hz, 1H), 3.69 (d, J=12.4 Hz, 2H), 3.22-3.08 (m, 3H), 2.96 (s, 3H), 2.88(s, 3H), 2.24 (d, J=14.1 Hz, 2H), 2.16-2.02 (m, 2H), 1.71 (d, J=6.6 Hz,6H). LCMS calc. for C₂₅H₂₉F₃N₇S [M+H]⁺: m/z=516.2; Found: 515.9.

Example 121.N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine

Step 1. 3-Iodo-7-propan-2-ylthieno[3,2-b]pyridine

To a solution of 7-propan-2-ylthieno[3,2-b]pyridine (570 mg, 3.22 mmol)in trifluoromethanesulfonic acid (1.71 mL, 19.4 mmol) was addedN-iodosuccinimide (720 mg, 3.22 mmol) portion-wise. The reaction mixturewas stirred at room temperature for 1 h. The reaction was quenched withsat. NaHCO₃ (aq.) (20 mL) and extracted with EtOAc (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography(3-30% EtOAc/heptane) and further purified by prep-HPLC on a C18 column(20-100% MeCN/0.1% TFA(aq.)) to afford the title compound as a TFA salt(680 mg, 1.63 mmol, 50.6% yield), a red oil. LCMS calc. for C₁₀H₁₁INS[M+H]⁺: m/z=304.0; Found: 304.1.

Step 2. 7-Propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridine

A mixture of 3-iodo-7-propan-2-ylthieno[3,2-b]pyridine, TFA salt (250mg, 0.599 mmol, from Step 1), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (607 mg, 3.16 mmol), andcopper(I) iodide (628 mg, 3.30 mmol) in DMF (3 mL) was stirred at 100°C. overnight. The reaction was quenched with water (5 mL), and themixture extracted with EtOAc (5 mL×3). The combined organic layers weredried over Na₂SO₄, filtered, and concentrated. The residue was purifiedby prep-HPLC on a C₁₈ column (10-100% MeCN/0.1% TFA (aq.)) to yield thetitle compound as a TFA salt (30.1 mg, 0.0838 mmol, 14.0% yield). LCMScalc. for C₁₁H₁₁F₃NS [M+H]⁺: m/z=246.1; Found 246.1.

Step 3.2-(2-Chloro-5-fluoro-3,4-dihydropyrimidin-4-yl)-7-isopropyl-3-(trifluoromethyl)thieno[3,2-b]pyridine

A solution of 7-propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridine,TFA salt (25.0 mg, 0.0696 mmol, from Step 2) in THE (2 mL) was addedlithium diisopropylamide (0.25 mL, 0.50 mmol, 2.0 M inTHF/ethylbenzene/hexanes) dropwise at −78° C. The resulting solution wasstirred at −78° C. for 10 min. Then 2-chloro-5-fluoropyrimidine (10.3mg, 0.153 mmol) was added, and the resulting solution was stirred at−78° C. After stirring for 20 min, the reaction mixture was slowlywarmed to room temperature. The reaction was quenched with sat. NH₄Cl(aq.) (10 mL) and extracted with EtOAc (20 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated to afford thetitle compound, which was used without further purification. LCMS calc.for C₁₅H₁₃ClF₄N₃S [M+H]⁺: m/z=378.0, 380.0; Found 378.0, 380.0.

Step 4.2-(2-Chloro-5-fluoropyrimidin-4-yl)-7-propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridine

To a solution of2-(2-chloro-5-fluoro-1,6-dihydropyrimidin-6-yl)-7-propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridine(from Step 5) in THE (5 mL) was added 2,3dichloro-5,6-dicyano-p-benzoquinone (14.4 mg, 0.0634 mmol). Theresulting mixture was stirred at room temperature for 1 h. The reactionwas diluted with EtOAc (30 mL) and sat. NaHCO₃ (aq.) (30 mL). Theorganic layer was separated, and the aqueous layer was extracted withEtOAc (30 mL). The combined organic layers were dried over sodiumNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (1-30% EtOAc/heptane) to afford the title compound(19.2 mg, 0.0511 mmol, 73.4% yield over two steps) as a yellow oil. ¹HNMR (300 MHz, CD₃OD) δ 8.92 (t, J=1.1 Hz, 1H), 8.80 (d, J=4.9 Hz, 1H),7.55 (d, J=4.9 Hz, 1H), 3.41-3.20 (m, 1H), 1.48 (d, J=6.9 Hz, 6H). LCMScalc. for C₁₅H₁₁ClF₄N₃S [M+H]⁺: m/z=376.0, 378.0; Found 375.8, 377.8.

Step 5.N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 1, Step 8 to afford the title compound as a TFAsalt. ¹H NMR (300 MHz, CD₃OD) δ 8.90 (d, J=1.5 Hz, 1H), 8.82 (d, J=4.9Hz, 1H), 8.22 (dd, J=9.6, 2.9 Hz, 1H), 7.93 (d, J=2.9 Hz, 1H), 7.63 (d,J=9.6 Hz, 1H), 7.56 (d, J=4.9 Hz, 1H), 4.09-3.51 (m, 6H), 3.40-3.34 (m,2H), 3.30-3.25 (m, 3H), 1.49 (d, J=6.9 Hz, 6H), 1.42 (t, J=7.3 Hz, 3H).LCMS calc. for C₂₆H₂₈F₄N₇S [M+H]⁺: m/z=546.2; Found 546.1.

Example 122.2-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropylthieno[3,2-b]pyridine-3-carbonitrile

Step 1. 7-Propan-2-ylthieno[3,2-b]pyridine-3-carbonitrile

A mixture of 3-iodo-7-propan-2-ylthieno[3,2-b]pyridine (1.4 g, 4.6 mmol,Example 121, Step 1), zinc cyanide (250 mg, 2.13 mmol), XPhos Pd G3(0.39 g, 0.46 mmol, CAS: 1445085-55-1), and N,N-diisopropylethylamine(0.91 mL, 5.5 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 85°C. overnight. The reaction was quenched with water (20 mL) and extractedwith EtOAc (20 mL×3). The combined organic layers were washed with brine(30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (0-20% EtOAc/heptane) to affordthe title compound (174 mg, 0,860 mmol, 18.6% yield). LCMS calc. forC₁₁H₁₁N₂S [M+H]⁺: m/z=203.1; Found 203.1.

Step 2.7-Isopropyl-2-(tributylstannyl)thieno[3,2-b]pyridine-3-carbonitrile

To a solution of 7-propan-2-ylthieno[3,2-b]pyridine-3-carbonitrile (40.1mg, 0.198 mmol) in THE (1 mL) was added lithium diisopropylamide (0.11mL, 0.22 mmol, 2.0 M in THF/ethylbenzene/hexanes) dropwise at −78° C.The mixture was stirred at −78° C. for 30 min. Thentributyl(chloro)stannane (0.060 mL, 0.22 mmol) was added. The mixturewas stirred at room temperature for 1 h. The reaction was quenched withKF (aq.) (1 mL, 0.3 mmol, 0.3 N) and stirred at room temperature for 1h. Then the mixture was passed through a Celite pad and extracted withEtOAc (1 mL×3). The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The residue was purified by silica gelchromatography (0-10% EtOAc/hexane) to give the title compound (72.0 mg,0.146 mmol, 73.9% yield) as a colorless oil. R_(f)=0.5 (10%EtOAc/hexane).

Step 3.2-(2-Chloro-5-fluoropyrimidin-4-yl)-7-isopropylthieno[3,2-b]pyridine-3-carbonitrile

A mixture of7-propan-2-yl-2-tributylstannylthieno[3,2-b]pyridine-3-carbonitrile(72.0 mg, 0.146 mmol), 2,4-dichloro-5-fluoropyrimidine (48.9 mg, 0.293mmol), and tetrakis(triphenylphosphine)palladium(0) (25.4 mg, 0.0220mmol) in toluene (1 mL) was stirred at 100° C. overnight. The solventwas removed, and the residue was purified by silica gel chromatography(0-35% EtOAc/hexane) to give the title compound (27.2 mg, 0.0817 mmol,55.9% yield) as a colorless solid. LCMS calc. for C₁₅H₁₁ClFN₄S [M+H]⁺:m/z=333.0; Found: 332.9.

Step 4.2-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropylthieno[3,2-b]pyridine-3-carbonitrile

The title compound was synthesized by procedures analogous to thoseoutlined in Example 1, Step 8 to afford the title compound as a TFAsalt. ¹H NMR (300 MHz, CD₃OD) δ 8.98 (d, J=2.7 Hz, 1H), 8.86 (d, J=4.9Hz, 1H), 8.18 (dd, J=9.5, 2.9 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.74 (d,J=9.5 Hz, 1H), 7.60 (d, J=4.9 Hz, 1H), 4.09-3.52 (m, 4H), 3.50-3.33 (m,7H), 1.50 (d, J=6.9 Hz, 6H), 1.43 (t, J=7.3 Hz, 3H). LCMS calc. forC₂₆H₂₈FN₈S [M+H]⁺: m/z=503.2; Found 503.1.

Example 123.5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propan-2-ylthieno[3,2-c]pyridin-2-yl)pyrimidin-2-amine

Step 1. 2,4-Dibromo-3-methyl-7-propan-2-ylthieno[3,2-c]pyridine

A mixture of2-bromo-3-methyl-7-propan-2-yl-5H-thieno[3,2-c]pyridin-4-one (250 mg,0.874 mmol, Example 51, Step 4) and phosphoryl bromide (376 mg, 1.31mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. for 5 h. The reactionwas quenched with ice-cold water (3 mL) and extracted with EtOAc (3mL×3). The combined organic layers were washed with sat. NaHCO₃ (aq.) (5mL) and brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography (0-30% EtOAc/heptane)to afford the title compound (202 mg, 0.579 mmol, 66.2% yield). LCMScalc. for C₁₁H₁₂Br₂NS [M+H]⁺: m/z=347.9, 349.9, 351.9; Found: 347.8,349.8, 351.8.

Step 2. 3-Methyl-7-propan-2-ylthieno[3,2-c]pyridine

To a solution of 2,4-dibromo-3-methyl-7-propan-2-ylthieno[3,2-c]pyridine(200 mg, 0.573 mmol) in methanol (1 mL) was added Pd/C (20.0 mg, 0.0188mmol, 10 wt %) and triethylamine (0.226 mL, 1.15 mmol). The reactionmixture was stirred under an atmosphere of hydrogen overnight. Thereaction mixture was filtered, and the filtrate was concentrated. Theresidue was purified by silica gel chromatography (0-30% EtOAc/heptane)to afford the title compound (55.1 mg, 0.288 mmol, 50.2% yield). LCMScalc. for C₁₁H₁₄NS [M+H]⁺: m/z=192.1; Found: 191.8.

Step 3.2-(2-Chloro-5-fluoro-1,6-dihydropyrimidin-6-yl)-3-methyl-7-propan-2-ylthieno[3,2-c]pyridine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 121, Step 3. LCMS calc. for C₁₅H₁₆ClFN₃S [M+H]⁺:m/z=324.1, 326.1; Found: 323.9, 325.9.

Step 4.2-(2-Chloro-5-fluoropyrimidin-4-yl)-3-methyl-7-propan-2-ylthieno[3,2-c]pyridine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 121, Step 4. LCMS calc. for C₁₅H₁₄ClFN₃S [M+H]⁺:m/z=322.1, 324.1; Found: 321.9, 323.8.

Step 5.5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propan-2-ylthieno[3,2-c]pyridin-2-yl)pyrimidin-2-amine

The title compound was synthesized by procedures analogous to thoseoutlined in Example 1, Step 8 to afford the title compound as a TFAsalt. ¹H NMR (300 MHz, CD₃OD) δ 9.47 (s, 1H), 8.96 (d, J=1.9 Hz, 1H),8.65 (s, 1H), 8.37-8.27 (m, 2H), 7.77 (d, J=8.9 Hz, 1H), 3.72 (d, J=12.5Hz, 2H), 3.56-3.50 (m, 1H), 3.26-3.18 (m, 2H), 3.16-3.09 (m, 1H), 2.98(s, 3H), 2.87 (d, J=2.9 Hz, 3H), 2.31-2.19 (m, 2H), 2.16-2.04 (m, 2H),1.60 (d, J=6.9 Hz, 6H). LCMS calc. for C₂₆H₃₀FN₆S [M+H]⁺: m/z=477.2;Found: 477.1.

Example 124.N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

Step 1. 2-[Formyl(propan-2-yl)amino]-4-methylthiophene-3-carboxylic Acid

To a solution of formic acid (1.00 mL, 0.264 mmol) in chloroform (20 mL)was added EDC (4.1 g, 0.26 mmol) at −15° C. The reaction vessel wasremoved from the cooling bath, and the reaction mixture stirred at roomtemperature for 10 min. A solution of4-methyl-2-(propan-2-ylamino)thiophene-3-carboxylic acid (39.3 g, 197mmol) in chloroform (2.5 L) was then added. The reaction solution wasstirred at room temperature for 20 min, and another portion of formicacid (1.00 mL, 0.264 mmol) and EDC (4.10 g, 0.260 mmol) were added. Thisprocedure was repeated 12 times. Upon stirring overnight, the reactionmixture was diluted with water and 1 N HCl (aq.). The resulting mixturewas extracted with DCM (3×). The combined organic layers were dried overNa₂SO₄. After removal of solvent, the residue was purified by silicachromatography (5%-100% EtOAc/heptanes, then 2% AcOH in EtOAc to affordthe title compound (26.5 g, 117 mmol, 59.1%). LCMS calc. for C₁₀H₁₄NO₃S[M+H]⁺: m/z=228.2; Found: 228.1.

Step 2. N-(3-amino-4-methylthiophen-2-yl)-N-propan-2-ylformamide

To a solution of2-[formyl(propan-2-yl)amino]-4-methylthiophene-3-carboxylic acid (2.40g, 10.6 mmol) and triethylamine (4.42 mL, 31.7 mmol) in 1,4-dioxane (150mL) was added diphenylphosphoryl azide (3.41 mL, 15.8 mmol). Thereaction mixture was stirred at room temperature for 1 h. Water (150 mL)was added, and the reaction mixture was stirred at 100° C. overnight.The reaction mixture was concentrated under reduced pressure andextracted with DCM (3×). The combined organic phases were dried overNa₂SO₄. After removal of solvent, the residue was purified by silica gelcolumn chromatography (5%-60% EtOAc/heptane with 0.1% Et₃N) to affordthe title compound (9.80 g). While not analytically pure, the materialwas used in the next step without further purification. LCMS calc. forC₉H₁₅N₂OS [M+H]⁺: m/z=199.1; Found: 198.9.

Step 3. 6-Methyl-3-propan-2-ylthieno[2,3-d]imidazole

A mixture of N-(3-amino-4-methylthiophen-2-yl)-N-propan-2-ylformamide(19.0 g, 95.8 mmol) and POCl₃ (8.93 mL, 95.8 mmol) in toluene (150 mL)was stirred at 100° C. overnight. 10% Na₂CO₃ (aq.) was added, and themixture was extracted with DCM (3×). The combined organic phases weredried over Na₂SO₄. After removal of solvent, the residue was purified bysilica gel column chromatography (5%-80% EtOAc/heptanes) to afford thetitle compound (12.4 g, 68.8 mmol, 71.8%). LCMS calc. for C₉H₁₃N₂S[M+H]: m/z=181.1; Found: 181.2.

Step 4.6-Methyl-3-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[2,3-d]imidazole

The title compound was synthesized according to procedures analogous toExample 52, Step 6. LCMS calc. for C₁₅H₂₄BN₂O₂S [M+H]⁺: m/z=307.2 Found:307.1.

Step 5.5-(2-Chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-propan-2-ylthieno[2,3-d]imidazole

The title compound was synthesized according to procedures analogous toExample 52, Step 6 to afford the title compound as a TFA salt. ¹H NMR(300 MHz, CDCl₃) δ 8.42 (dd, J=3.0, 0.7 Hz, 1H), 7.77 (s, 1H), 4.55(hept, J=6.9 Hz, 1H), 2.74 (d, J=3.4 Hz, 3H), 1.62 (d, J=6.7 Hz, 6H).LCMS calc. for C₁₃H₁₃ClFN₄S [M+H]⁺: m/z=311.1 Found: 310.9.

Step 6.N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 1, Step 8 to afford the title compound as an HCl salt (630 mg,1.27 mmol, 99%). ¹H NMR (300 MHz, CD₃OD) δ 9.00 (s, 1H), 8.81 (d, J=3.0Hz, 1H), 8.36 (m, 2H), 7.65 (d, J=8.9 Hz, 1H), 4.95-4.90 (m, 1H), 3.79(s, 2H), 3.57 (br s, 2H), 3.27-3.11 (m, 6H), 2.76 (d, J=3.0 Hz, 3H),2.65 (m, 2H), 1.70 (d, J=6.7 Hz, 6H), 1.37 (t, J=7.3 Hz, 3H). LCMS calc.for C₂₅H₃₂FN₈S [M+H]+: m/z=495.2; Found: 495.2.

Example 125.5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine(Isomer 1)

Step 1. Tert-Butyl5-(6-chloropyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

A suspension of 5-bromo-2-chloropyridine (6.00 g, 31.2 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(9.64 g, 31.18 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.14 g,1.56 mmol), and potassium carbonate (17.24 g, 124.7 mmol) in 1,4-dioxane(90 mL) and water (30 mL) was stirred at 100° C. under a nitrogenatmosphere for 6 h. The reaction mixture was cooled to room temperature,concentrated, partitioned between EtOAc (100 mL) and water (100 mL), andfiltered through a pad of celite. The organic layer was separated, andthe aqueous layer was extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with brine (100 mL), dried over Na₂SO₄, andconcentrated to give a dark brown residue. The residue was purified bysilica column chromatography (0-30% EtOAc/heptanes) to give the titlecompound (8.63 g, 29.3 mmol, 93.9% yield) as a colorless solid. LC-MScalc. for C₁₅H₂₀ClN₂O₂[M+H]⁺: m/z=295.1; Found: 294.9.

Step 2. Tert-Butyl-3-(6-chloropyridin-3-yl)piperidine-1-carboxylate(Isomers 1 and 2)

To a solution of tert-butyl5-(6-chloropyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (7.70 g,26.1 mmol) in EtOAc (100 mL) was added PtO₂ (770 mg, 3.39 mmol). Themixture was stirred under a hydrogen atmosphere overnight. Thesuspension was filtered through Celite and concentrated to give thetitle compound (7.00 g, 23.6 mmol, 90.0% yield) as a gray oil. Theisomers were separated using SFC on a Columntek Enantiocel A6 column(35% MeOH/CO₂, 100 bar) to afford the title compound as two isomers:isomer 1 (3 g) and isomer 2 (3 g). Isomer 1: LC-MS calc. forC₁₅H₂₂ClN₂O₂[M+H]⁺: m/z=297.1; Found: 296.9. Isomer 2: LC-MS calc. forC₁₅H₂₂ClN₂O₂[M+H]⁺: m/z=297.1; Found: 296.9.

Step 3.5-Fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 53, Step 1. LCMS calc. for C₁₃H₁₄FN₅S [M+H]⁺: m/z=292.1; Found:292.0.

Step 4.5-Fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-[-piperidin-3-yl]pyridin-2-yl]pyrimidin-2-amine(Isomer 1)

A sealed tube was charged with5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine(53 mg, 0.18 mmol),tert-butyl-3-(6-chloropyridin-3-yl)piperidine-1-carboxylate (isomer 1)(56 mg, 0.19 mmol), XPhos Pd G2 (33 mg, 0.040 mmol, CAS 1310584-14-5),sodium tert-butoxide (69 mg, 0.72 mmol), and 1,4-dioxane (1 mL). Themixture was heated under a nitrogen atmosphere for 4 h. The solvent wasremoved under reduced pressure. To the resulting residue was added TFA(5 mL). The mixture was stirred for 10 min. The solvent was removedunder reduced pressure. The crude material was purified by prep-HPLC ona C₁₈ column (2-25% MeCN/0.1% TFA (aq)) to yield the title compound asthe TFA salt (90.0 mg, 0.190 mmol, quantitative). LC-MS calc. forC₂₃H₂₇FN₇S [M+H]⁺: m/z=452.2; Found: 452.0.

Step 5.5-Fluoro-N-[5-[1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine(Isomer 1)

To a suspension of5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-[piperidin-3-yl]pyridin-2-yl]pyrimidin-2-amine(isomer 1) (90 mg, 0.20 mmol) in methanol (3 mL) was added acetic acid(34.2 μL, 0.600 mmol), NaBH₃CN (63 mg, 1.0 mmol), and formaldehyde (74.2uL, 1.00 mmol, 37 wt % aq.). The reaction mixture was stirred for 30min. To the mixture was added MeCN (2 mL) and water (0.5 mL). Themixture was purified by prep-HPLC on C18 column (2 to 25% MeCN/0.1% TFA(aq)). The product-containing fractions were combined and concentrated,basified with NaHCO₃, and extracted with DCM (3×20 mL). The combinedorganic phases were dried over Na₂SO₄ and concentrated to give a yellowoil, which was then dissolved in EtOAc (1 mL). The desired productprecipitated from the solution after 2 min. The resulting solid wasdissolved in water (1 mL) and 2N HCl (0.23 mL, 2.3 equiv) andconcentrated under reduced pressure to give the title compound (24.4 mg,0.0524 mmol, 23% yield) as the HCl salt, a yellow solid. ¹H NMR (300MHz, CD₃OD) δ 8.75 (d, J=3.2 Hz, 1H), 8.66 (s, 1H), 8.39-8.26 (m, 2H),7.69 (d, J=8.9 Hz, 1H), 4.80-4.78 (m, 1H), 3.73-3.50 (m, 2H), 3.25-3.18(m, 2H), 3.17-3.01 (m, 1H), 2.94 (s, 3H), 2.76 (d, J=3.0 Hz, 3H),2.21-2.06 (m, 2H), 2.05-1.93 (m, 1H), 1.91-1.76 (m, 1H), 1.67 (d, J=6.7Hz, 6H). LC-MS calc. for C₂₄H₂₉FN₇S [M+H]⁺: m/z=466.2; Found: 466.2.

Example 126.5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine(Isomer 2)

The title compound was synthesized according to procedures analogous toExample 125, Steps 4-5, utilizingtert-butyl-3-(6-chloropyridin-3-yl)piperidine-1-carboxylate (isomer 2)in Step 4, to afford the title compound as the HCl salt. ¹H NMR (300MHz, CD₃OD) δ 8.74 (d, J=3.2 Hz, 1H), 8.59 (s, 1H), 8.36-8.25 (m, 2H),7.70 (d, J=9.0 Hz, 1H), 4.81-4.75 (m, 1H), 3.71-3.56 (m, 2H), 3.26-3.19(m, 2H), 3.14-3.02 (m, 1H), 2.95 (s, 3H), 2.76 (d, J=3.0 Hz, 3H), 2.11(d, J=14.1 Hz, 2H), 2.05-1.96 (m, 1H), 1.92-1.76 (m, 1H), 1.66 (d, J=6.7Hz, 6H). LC-MS calc. for C₂₄H₂₉FN₇S [M+H]⁺: m/z=466.2; Found: 466.2.

Example 127.4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-methoxy-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 52 to afford the title compound as a TFA salt. ¹H NMR (300 MHz,DMSO-d₆) δ 11.38 (s, 1H), 10.11 (s, 1H), 8.51 (s, 1H), 8.24 (s, 2H),8.09 (dd, J=9.0, 2.1 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 4.84 (hept, J=6.3Hz, 1H), 4.14 (s, 3H), 3.54 (d, J=11.9 Hz, 2H), 3.08 (q, J=10.4 Hz, 2H),2.94-2.86 (m, 1H), 2.81 (d, J=4.1 Hz, 3H), 2.71 (s, 3H), 2.07 (d, J=13.6Hz, 2H), 2.00-1.84 (m, 2H), 1.55 (d, J=6.6 Hz, 6H). LCMS calc. forC₂₅H₃₂N₇OS [M+H]⁺: m/z=478.24; Found: 478.20.

Example 128.N-(5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 124 to afford the title compound as an HCl salt. ¹H NMR (300MHz, CD₃OD) δ 8.47 (d, J=3.2 Hz, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.21 (d,J=2.1 Hz, 1H), 8.05 (s, 1H), 7.71 (dd, J=8.7, 2.4 Hz, 1H), 4.78-4.64 (m,1H), 3.60 (d, J=12.3 Hz, 2H), 3.14 (q, J=7.3 Hz, 2H), 3.04-2.83 (m, 3H),2.60 (d, J=3.8 Hz, 3H), 2.18-1.89 (m, 4H), 1.62 (d, J=6.7 Hz, 6H), 1.37(t, J=7.3 Hz, 3H). LCMS calc. for C₂₅H₃₁FN₇S [M+H]⁺: m/z=480.2; Found:480.2.

Example 129.N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 124 to afford the title compound as the tartaric acid salt. ¹HNMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H), 8.54 (d, J=3.5 Hz, 1H), 8.16 (s,1H), 7.99 (d, J=8.9 Hz, 1H), 7.94 (d, J=1.5 Hz, 1H), 7.61 (d, J=2.9 Hz,1H), 7.03 (dd, J=8.9, 3.0 Hz, 1H), 4.73 (hept, J=6.7 Hz, 1H), 4.09 (s,2H), 4.05 (s, 4H), 4.00 (s, 4H), 2.99 (q, J=7.2 Hz, 2H), 1.55 (d, J=6.6Hz, 6H), 1.03 (t, J=7.2 Hz, 3H). LCMS calc. for C₂₄H₂₈FN₈S [M+H]⁺:m/z=479.21; Found: 478.77.

Example 130.5-Chloro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine

The title compound was synthesized according to procedures analogous toExample 124 to afford the title compound as a TFA salt. ¹H NMR (300 MHz,DMSO-d₆) δ 10.47 (s, 1H), 9.56 (s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.24(d, J=2.1 Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.76 (dd, J=8.7, 2.2 Hz, 1H),4.77 (hept, J=6.6 Hz, 1H), 3.50 (t, J=11.3 Hz, 2H), 3.85-3.20 (m, 3H),2.80 (d, J=4.4 Hz, 3H), 2.44 (s, 3H), 2.05-1.59 (m, 4H), 1.54 (d, J=6.6Hz, 6H). LC-MS calc. for C₂₄H₂₉ClN₇S [M+H]⁺: m/z=482.19; Found 482.20.

Example 131.2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]pyridine5-oxide

The title compound was synthesized according to procedures analogous toExample 50 to afford the title compound as a TFA salt. ¹H NMR (300 MHz,CD₃OD) δ 9.07 (s, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.40-8.30 (m, 3H), 7.67(d, J=9.0 Hz, 1H), 3.70 (d, J=12.5 Hz, 2H), 3.27-3.06 (m, 4H), 2.97 (s,3H), 2.72 (d, J=2.8 Hz, 3H), 2.25 (d, J=14.1 Hz, 2H), 2.15-2.05 (m, 2H),1.52 (d, J=6.9 Hz, 6H).

Example A: Enzymatic Activity and Cytotoxicity Studies CDK4/CyclinD1Enzymatic Activity Assay

The inhibitory activity of compounds was evaluated in vitro usingTR-FRET assay with white 384-well low volume microplate (GreinerBio-One). CDK4/Cyclin D1 catalyzed phosphorylation of peptide in thepresence and absence of compounds was measured. IC₅₀ determination.Recombinant protein complex CDK4/Cyclin D1, expressed from insect cell,was purchased from ProQinase. Testing compounds were dissolved in DMSOat 0.1 mM and tested in 9-dose IC₅₀ mode. The reaction mixture wasprepared by mixing CDK4/CyclinD1 (1 nM final), ULight-4E-BP1 (100 nMfinal, Perkinelmer, TRF0128-D), and ATP (2 mM final) in assay buffer (20mM of HEPES pH 7.4, 1 mM of EGTA, 0.05% BSA, 0.005% Tween 20, and 1 mMTCEP). The compound of interest in DMSO was added to each well in 3-foldserial dilution by dispenser (TECAN D300E). After 20 minutespreincubation at room temperature, MgCl₂ (10 mM final) was added toinitiate the reaction. Following a 60 minutes incubation at 37° C., thereaction was stopped by addition of 2 μL of quenching buffer consistingof Lance detection buffer (Perkinelmer CR97-100C), 2 nM LANCE UltraEuropium-anti-P-4E-BP1 (Perkinelmer, TRF0216-D), 10 mM EDTA, andincubate at room temperature for additional 60 minutes in dark. Thereaction signal was measured by Envision multimode plate reader(PerkinElmer, 2102-0010). IC₅₀ values were determined by fitting thedata to the standard 4 parameters with Hill Slope using GraphPad Prismsoftware. Table 4, below, shows the IC₅₀ values determined by thisassay.

CDK6/CyclinD1 Enzymatic Activity Assay

The inhibitory activity of compounds was evaluated in vitro usingTR-FRET assay with white 384-well low volume microplate (GreinerBio-One). CDK6/Cyclin D1 catalyzed phosphorylation of peptide in thepresence and absence of compounds was measured and used in IC₅₀determination. Recombinant protein complex CDK6/Cyclin D1, expressedfrom insect cell, was purchased from ProQinase. Testing compounds weredissolved in DMSO at 0.1 mM and tested in 9-dose IC50 mode. The reactionmixture was prepared by mixing CDK6/Cyclin D1 (1 nM final),ULight-4E-BP1 (100 nM final, Perkinelmer, TRF0128-D), and ATP (250 μMfinal) in assay buffer (20 mM of HEPES pH 7.4, 1 mM of EGTA, 0.05% BSA,0.005% Tween 20, and 1 mM TCEP). The compound of interest in DMSO wasadded to each well in 3-fold serial dilution by dispenser (TECAN D300E).After 20 minutes preincubation at room temperature, 0.1 μL MgCl₂ (10 mMfinal) was added to initiate the reaction. Following a 60 minutesincubation at 37° C., the reaction was stopped by addition of 2 μL ofquenching buffer consisting of Lance detection buffer (PerkinelmerCR97-100C), 2 nM LANCE Ultra Europium-anti-P-4E-BP1 (Perkinelmer,TRF0216-D), 10 mM EDTA, and incubate at room temperature for additional60 minutes in dark. The reaction signal was measured by Envisionmultimode plate reader (PerkinElmer, 2102-0010). IC₅₀ values weredetermined by fitting the data to the standard 4 parameters with HillSlope using GraphPad Prism software. Table 4, below, shows the IC₅₀values determined by this assay.

Cell Proliferation Studies in MCF7 Cells

Cell proliferation studies were conducted in MCF7 adenocarcinoma cellline. Cells were maintained in DMEM (Coming, Catalog #: 10-013-CV)supplemented with 10% v/v FBS (Gibco, Catalog #: 26140-079), 1% v/vPenicillin Streptomycin (Gibco, Catalog#15140-122) Cells were seeded in384-well plates at a density of 100 or 200 cells/well. Compoundsdissolved in DMSO were plated in quadruplicate using a digital dispenser(D300E, Tecan) and tested on a 9-point 3-fold serial dilution. Cellswere incubated for 10 days in a 37° C. active humidified incubator at 5%CO₂. A media exchange and second compound addition were performed on day5. Cell viability was measured using the ATP-Lite 1-Step Luminescencereagent (Perkin Elmer, Catalog #: 6016731) as per manufacturer'sinstructions. Luminescence signal was measured with a multimode platereader (Envision 2105, Perkin Elmer). Raw data files were imported toDotmatics Screening Ultra for IC₅₀ analysis. Luminescence values werenormalized to both background and DMSO controls to obtain a percentageof viable cells relative to DMSO vehicle control. The results are shownin Table 7, below.

TABLE 7 IC₅₀ Values CDK4_D1 CDK6_D1 PROLIFERATION_CTG_MCF7 Example IC₅₀(nM) IC₅₀ (nM) IC₅₀ (nM) 1 ++++ +++ +++ 2 ++++ ++++ ++++ 3 ++++ +++ +++4 ++++ ++++ +++ 5 +++ — +++ 6 ++++ — +++ 7 ++++ — +++ 8 ++++ — +++ 9++++ ++++ ++++ 10 ++++ — ++ 11 +++ — ++ 12 ++ — — 13 ++++ — +++ 14 ++++— +++ 15 ++++ — — 16 ++++ — +++ 17 ++++ +++ +++ 18 +++ — +++ 19 +++ — ++20 ++++ — +++ 21 ++++ — +++ 22 +++ — ++ 23 ++++ +++ +++ 24 +++ — ++ 25+++ — +++ 26 ++++ — +++ 27 +++ — ++ 28 +++ — ++ 29 +++ — +++ 30 ++++ ++++++ 31 +++ — ++ 32 ++++ — ++ 33 ++++ — ++ 34 ++++ — +++ 35 ++++ — — 36+++ — ++ 37 +++ — ++ 38 +++ — + 39 +++ — ++ 40 +++ — + 41 ++ — + 42 ++— + 43 +++ — ++ 44 +++ — ++ 45 +++ — ++ 46 +++ — ++ 47 +++ — ++ 48 ++ —++ 49 ++ — ++ 50 ++++ ++++ ++++ 51 ++++ ++++ +++ 52 ++++ ++++ ++++ 53++++ ++++ +++ 54 ++++ +++ +++ 55 ++++ ++++ +++ 56 ++++ ++++ +++ 57 ++++++++ +++ 58 ++++ +++ +++ 59 ++++ +++ +++ 60 ++++ ++++ ++++ 61 ++++ ++++++++ 62 ++++ ++++ +++ 63 +++ — ++ 64 +++ +++ ++ 65 +++ — — 66 +++ +++ —67 ++++ ++++ +++ 68 +++ — — 68 ++++ ++++ +++ 70 ++++ — — 71 ++++ +++ +++72 ++++ ++++ +++ 73 ++++ +++ +++ 74 ++++ +++ +++ 75 ++++ ++++ ++++ 76++++ — — 77 ++++ ++++ +++ 78 ++++ ++++ +++ 79 ++++ ++++ +++ 80 +++ +++++ 81 ++++ ++++ +++ 82 ++++ ++++ +++ 83 ++++ — +++ 84 ++++ ++++ +++ 85++++ — +++ 86 ++++ +++ +++ 87 ++++ ++++ +++ 88 ++++ +++ +++ 89 ++++ +++++++ 90 ++++ +++ +++ 91 ++++ ++++ +++ 92 ++++ ++++ +++ 93 ++++ +++ +++ 94++++ ++++ +++ 95 ++++ +++ +++ 96 +++ — ++ 97 ++++ ++++ ++++ 98 ++++ —+++ 99 ++++ +++ +++ 100 +++ — ++ 101 +++ — — 102 ++++ ++++ +++ 103 ++ —— 104 +++ — — 105 ++++ — +++ 106 ++ — — 107 +++ — — 108 ++++ +++ +++ 109++++ +++ +++ 110 ++ — — 111 +++ — +++ 112 ++++ +++ +++ 113 ++ — — 114++++ +++ +++ 115 ++++ — +++ 116 ++++ — — 117 ++++ — — 118 ++++ — ++ 119++ — — 120 ++++ ++++ +++ 121 ++++ +++ +++ 122 +++ — — 123 ++++ +++ +++124 ++++ ++++ +++ 125 ++++ ++++ +++ 126 ++++ ++++ +++ 127 +++ — — 128++++ ++++ ++++ 129 ++++ ++++ ++++ 130 ++++ +++ +++ 131 +++ — — In Table7, a “+” denotes an IC₅₀ value of >2000 nM; a “++” denotes an IC₅₀ valueof 200 nM < IC₅₀ ≤ 2000 nM; a “+++” denotes an IC₅₀ value of 20 nM <IC₅₀ ≤ 200 nM; and a “++++” denotes an IC₅₀ value of ≤20 nM.

Example B: Brain-to-Plasma Ratio Determination in Sprague-Dawley Rats

The brain-to-plasma ratio (K_(p)) was determined in male Sprague-Dawleyrats (7-9 weeks old) four hours after a single oral dose. Rats wereacclimated and given free access to standard rodent chow and waterthroughout the entire study. Test articles were formulated as a solutionat 0.3, 0.4, 0.5, or 1.0 mg/mL in a vehicle comprised of 10:15:75(v:v:v) dimethylacetamide (DMA):Solutol HS15:water and delivered orallyat a rate of 10 mL/kg to three rats to achieve final doses of 3, 4, 5,or 10 mg/kg, respectively. At 4 hours post-dose, blood samples werecollected via jugular vein cannula into tubes containing K₂EDTA as theanticoagulant and stored on ice. Blood samples were then centrifuged at4° C. at 6000 rpm for 5 minutes, and the resulting plasma was placedinto tubes and stored frozen at −80° C. until analysis. Whole brainsamples were also collected at 4 hours post-dose. The weight of eachbrain was measured and recorded, and samples were immediately stored ondry ice. Brain samples were then transferred to storage at −80° C. untilanalysis.

Prior to analysis, brain samples were combined with water (4 mL/1 gramof brain) and homogenized. Prior to injection, plasma and brainhomogenate samples and standards were prepared for analysis byprecipitation with acetonitrile or 1:1 (v:v) methanol:acetonitrile.Samples were then thoroughly mixed, centrifuged at 4000 rpm for 15minutes, and the resulting supernatant was transferred for analysis.Test article concentrations in plasma and brain homogenate were thendetermined by LC-MS/MS and quantified against calibration standardsprepared to known concentrations in matched blank (analyte-free)biological matrix. The K_(p) was then determined by dividing thedilution-corrected brain concentration by the plasma concentration fromeach rat. A brain density of 1 gram/mL was assumed for all calculations.

The results are shown in Table 8, below.

TABLE 8 K_(p) Values Example K_(p) 1 ++ 2 ++ 3 + 4 ++ 8 ++ 9 ++ 18 n.d.21 + 23 +++ 50 ++ 51 +++ 52 ++ 53 n.d. 54 + 55 +++ 56 +++ 57 ++ 60 + 61++ 62 n.d. 64 + 67 n.d. 68 ++ 71 n.d. 73 ++ 74 + 77 ++ 78 ++ 79 + 81n.d. 82 +++ 84 ++ 85 +++ 86 ++ 87 ++ 88 ++ 89 +++ 90 + 91 + 93 + 94 n.d.95 ++ 97 + 99 +++ 102 ++ 112 + 114 ++ 115 + 120 ++ 123 +++ 124 ++ 125 ++126 ++ 128 ++ 129 ++ 130 ++ In Table 8, a “+” denotes a K_(p) value<1.0; a “++” denotes 1.0 ≤ K_(p) < 3.0; a “+++” denotes K_(p) value≥3.0; and n.d. denotes a brain concentration below the detectable limit.

What is claimed:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate or N-oxide thereof,wherein ring A is a 5-7-membered heteroaryl; V=CL₁R₁ or N n is 1 or 2 or3; m is 1 or 2; is 1, 2, 3, 4, or 5; each L₁ is independently a bond, O,NR or C₁-C₆ alkylene, wherein R is H or C₁-C₆alkyl; each R₁ isindependently H, D, halogen, —OH, —CN, —NO₂, —C₁-C₆alkyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl, —OR^(a), —SR^(a), —NR^(c)R^(d),—NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(d),—S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅, —P(O)R^(b)R^(b),—P(O)(OR^(b))(OR^(b)), —B(OR^(c))(OR^(d)) or —S(O)₂R^(b); each R₂ isindependently H, D, halogen, C₁-C₈ alkoxide C₁-C₈ alkyl, haloalkyl, orCN and each R₃ is independently H, D, halogen, oxo, —OH, —CN, —NO₂,—C₁-C₆alkyl, —C₂-C₆alkenyl, —C₂-C₆alkynyl, C₀-C₁alk-aryl,C₀-C₁alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl, —OR^(a), —OR^(b), —SR^(b), —NR^(c)R^(d),—NR^(a)R^(c), —C(O)R^(b), —OC(O)R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(d),—S(O)R^(b), —S(O)₂NR^(c)R^(d), —S(O)(═NR)R^(b), —SF₅, —P(O)R^(b)R^(b),—P(O)(OR^(b))(OR), —B(OR^(d))(OR^(c)) or —S(O)₂R^(b); each R^(a) isindependently H, D, —C(O)R^(b), —C(O)OR^(c), —C(O)NR^(c)R^(d),—C(═NR)NR^(b)R^(c), —C(═NOR^(b))NR^(b)R^(c), —C(═NCN)NR^(b)R^(c),—P(OR^(c))₂, —P(O)R^(c)R^(b), —P(O)OR^(c)R^(b), —S(O)R^(b),—S(O)NR^(c)R^(d), —S(O)₂R^(b), —S(O)₂NR^(c)R^(d), SiR₃, —C₁-C₁₀alkyl,—C₂-C₁₀ alkenyl, —C₂-C₁₀ alkynyl, aryl, cycloalkyl, cycloalkenyl,heteroaryl, heterocycloalkyl, or heterocycloalkenyl; each R^(b), isindependently H, D, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, aryl,cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, orheterocycloalkenyl; each R^(c) or R^(d) is independently H, D, —C₁-C₁₀alkyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl, —OC₁-C₆alkyl, —O-cycloalkyl,aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl; or R^(c) and R^(d), together with the atom to whichthey are both attached, form a monocyclic or multicyclicheterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenylgroup; each R₄ is independently H, D, halogen, C₁-C₈ alkoxide or C₁-C₈alkyl, haloalkyl or CN.
 2. The compound of claim 1, wherein ring A is a5-membered heteroaryl having at least one N atom.
 3. The compound ofclaim 2, wherein the 5-membered heteroaryl having at least one N atom isan imidazole.
 4. The compound of claim 1, wherein ring A is a 6-memberedheteroaryl having at least one N atom.
 5. The compound of claim 4,wherein the 6-membered heteroaryl having at least two N atom is apyrimidine or a pyridazine.
 6. The compound of claim 1, wherein n is 1.7. The compound of claim 1, wherein n is
 2. 8. The compound of claim 1,wherein n is
 3. 9. The compound of claim 1, wherein m is
 1. 10. Thecompound of claim 1, wherein m is
 2. 11. The compound of claim 1,wherein o is
 1. 12. The compound of claim 1, wherein o is
 2. 13. Thecompound of claim 1, wherein o is
 3. 14. The compound of claim 1,wherein o is
 4. 15. The compound of claim 1, wherein o is
 5. 16. Thecompound of claim 1, wherein at least one R₂ is H.
 17. The compound ofclaim 1, wherein at least one R₂ is halogen.
 18. The compound of claim1, wherein at least one R₂ is C₁₋₆alkyl.
 19. The compound of claim 1,wherein at least one R₃ is H.
 20. The compound of claim 1, wherein atleast one R₃ is C₁₋₆alkyl.
 21. The compound of claim 1, wherein at leastone R₃ is C₃₋₁₀cycloalkyl.
 22. The compound of claim 1, wherein at leastone R³ is hydroxyalkyl.
 23. The compound of claim 1, wherein at leastone R³ is isopropyl.
 24. The compound of claim 1, wherein at least oneR³ is oxo bound to a nitrogen atom.
 25. The compound of claim 1, whereinat least one R₁ is an unsubstituted or substituted 6-memberedheterocyclalkyl.
 26. The compound of claim 25, wherein R₁ is anunsubstituted or substituted piperazine.
 27. The compound of claim 1,wherein at least one R₁ is an unsubstituted or substituted 7-memberedheterocycloalkyl.
 28. The compound of claim 1, wherein R₄ is hydrogen.29. The compound of claim 1, wherein R₄ is methyl.
 30. The compound ofclaim 1 in the form of a pharmaceutically acceptable salt.
 31. Thecompound of claim 1 that is a compound of formula II, formula III,formula IV, formula V, formula VI or formula VII:

or a pharmaceutically acceptable salt thereof, wherein each X isindependently N, N-oxide or CR₃ and at least one X is N or N-oxide; andeach Y is independently N or CR₃ and at least one Y is N.
 32. Thecompound of claim 1 that is a compound of formula VIII, formula IX,formula X, formula XI, formula XII, or formula XIII:

or a pharmaceutically acceptable salt thereof, wherein each X isindependently N, N-oxide or CR₃ and at least one X is N or N-oxide; andY is N or CHR₃.
 33. The compound of claim 1 that is a compound offormula XV, formula XVI, formula XVII, formula XVIII, formula XIX,formula XX, formula XXI, formula XXII, formula XXIII, formula XXIV,formula XXV, formula XXVI, or formula XXVII:

or a pharmaceutically acceptable salt thereof.
 34. The compound of claim1 that is a compound of formula XXIX, formula XXX, formula XXXI, orformula XXXII:

or a pharmaceutically acceptable salt thereof; wherein W is CH or N; Uis C(R₁₀)₂, NR₁₀, or O; R₁₀ is H, fluoro, C₁₋₆alkyl, or C₁₋₆alkoxide;and each g, h, j and k is independently 0, 1, 2 or
 3. 35. The compoundof claim 1 that is a compound of formula XXXV, formula XXXVI, formulaXXXVII, formula XXXVIII, formula XXXIX, formula XL, formula XLI, formulaXLII, formula XLIII, or formula XLIV:

or a pharmaceutically acceptable salt thereof; wherein W is CH or N; Uis C(R₁₀)₂, R₁₀ r O R₁₀ is H, fluoro, C₁₋₄alkyl or C₁₋₄alkoxide; andeach g, h, j and k is independently 0, 1, 2 or
 3. 36. The compound ofclaim 1 that is a compound of formula XLV, formula XLVI, formula XLVII,formula XLVIII, formula XLIX or formula L:

or a pharmaceutically acceptable salt thereof, wherein W is CH or N; Uis C(R₁₀)₂, NR₁₀ or O; R₁₀ is H, fluoro, C₁₋₄alkyl or C₁₋₄alkoxide. 37.The compound of claim 1 that is a compound of formula LI, formula LII,formula LIII, or formula LIV:

or a pharmaceutically acceptable salt thereof; wherein W is CH or N; Uis C(R₁₀)₂, NR₁₀ or O; R₁₀ is H, fluoro, C₁₋₄alkyl or C₁₋₄alkoxide. 38.The compound of claim 1 that is a compound of formula LVII, formulaLVIII, formula LIX, or formula LX:

or a pharmaceutically acceptable salt thereof; wherein R₁₀ is H,C₁₋₆alkyl, or C₁₋₆alkoxide.
 39. The compound of claim 1 that is acompound of formula LXIII, formula LXIV, formula LXV, formula LXVI,formula LXVII or formula LXVIII:

or a pharmaceutically acceptable salt thereof; wherein R₁₀ is H,C₁₋₄alkyl or C₁₋₄alkoxide.
 40. The compound of claim 1 that is:4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;N-(5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;4-(3-Cyclobutyl-2,6-dimethylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;4-(3-Cyclobutyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;4-(3-Cyclobutyl-2,6-dimethylthieno[2,3-d]imidazol-5-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;4-(3-Cyclopentyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;4-(3-Cyclopentyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(1-ethylpiperidin-4-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;2-[2-[2-[[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;N-[5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-(7-propan-2-ylthieno[3,2-b]pyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;2-[2-[2-[[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;2-[2-[2-[[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]propan-2-ol;4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;2-[2-[2-[[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]thieno[3,2-b]pyridin-7-yl]-1,1,1-trifluoropropan-2-ol;4-(3-Chloro-7-cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-N-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;N-(5-(2,6-Diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-4-(7-cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoropyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;4-(7-Cyclopentyl-3-methylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methoxypiperidin-1-yl)pyridin-2-yl]pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-5-fluoro-N-(5-morpholinopyridin-2-yl)pyrimidin-2-amine;4-(7-Cyclopentylthieno[3,2-b]pyridin-2-yl)-N-[5-(3,3-difluoropyrrolidin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-morpholin-4-ylpyridin-2-yl)pyrimidin-2-amine;4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine;4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-5-fluoro-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine;4-(4-Cyclopentylthieno[2,3-b]pyridin-2-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(7-Cyclopentyl-3-methylthieno[2,3-c]pyridin-2-yl)-5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine;4-(4-Cyclopentyl-7-methylthieno[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-(4-oxido-7-propan-2-ylthieno[3,2-b]pyridin-4-ium-2-yl)pyrimidin-2-amine;2-[5-Fluoro-2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]-3,5-dimethyl-7-propan-2-ylthieno[3,2-c]pyridin-4-one;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;6-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-N-(5-fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;(4-Ethylpiperazin-1-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone;4-(2,6-Dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(2-((5-(6-Ethyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;2-(2-((5-(4-Ethylpiperazine-1-carbonyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(6-methyl-2,6-diazaspiro[3.4]octan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;6-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropyl-5-methylthieno[2,3-d]pyrimidin-4(1H)-one;2-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[2,3-d]pyridazin-4(5H)-one;or a pharmaceutically acceptable salt thereof.
 41. The compound of claim1 that is:N-[5-[[4-(2,2-Difluoroethyl)piperazin-1-yl]methyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;1-[[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methyl]-N,N-dimethylpyrrolidine-3-carboxamide;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-pyridin-2-ylpyrimidin-2-amine;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2-yl]pyrimidin-2-amine;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(4-ethyl-6,6-difluoro-1,4-diazepan-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoro-N-[5-[2,2,3,3,5,5,6,6-octadeuterio-4-(trideuteriomethyl)piperazin-1-yl]pyridin-2-yl]pyrimidin-2-amine;N-[5-(5,5-Difluoro-7-methyl-2,7-diazaspiro[3.4]octan-2-yl)pyridin-2-yl]-4-(2,6-dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine;(6-Dthyl-2,6-diazaspiro[3.3]heptan-2-yl)-[6-[[5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]methanone;N-[5-[3-(Dimethylamino)azetidin-1-yl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;N-[5-[3-(Dimethylamino)pyrrolidin-1-yl]pyridin-2-yl]-4-(2,6-dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-amine;N-[5-(6-ethyl-3,6-Diazabicyclo[3.1.1]heptan-3-yl)pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;1-[6-[[4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-5-fluoropyrimidin-2-yl]amino]pyridin-3-yl]-4-methylpiperazin-2-one;2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-((3aS,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;2-(2-((5-(5-Ethyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-(methyl-d3)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(2-((5-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-(tetrahydrofuran-3-yl)piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methyl-5-(methyl-d3)thieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-5-methylthieno[3,2-c]pyridin-4(5H)-one;2-(2-((5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-methylpiperidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(2-((5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(6-isopropyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((6-(1-methylpiperidin-4-yl)pyridazin-3-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno [3,2-c]pyridin-4(5H)-one;2-(5-Fluoro-2-((5-(1-isopropylpyrrolidin-3-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3,5-dimethylthieno[3,2-c]pyridin-4(5H)-one;7-Isopropyl-5-methyl-2-(2-((5-(1-methylpiperidin-4-yl)pyridine-2-yl)amino) pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one;7-Isopropyl-5-methyl-2-(5-methyl-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)thieno[3,2-c]pyridin-4(5H)-one;4-(6-((5-Fluoro-4-(7-isopropyl-3,5-dimethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-2-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-1-methylpiperidine 1-oxide;5-Fluoro-4-(3-isopropyl-2-methyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;N-(5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine;4-(3-Cyclopropyl-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoropyrimidin-2-amine;2-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)-1,1,1-trifluoropropan-2-ol;1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-one;1-(5-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-3-yl)ethan-1-ol;N-(5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-(2-methoxypropan-2-yl)-2,6-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)pyrimidin-2-amine;4-(1,6-dimethyl-3-propan-2-ylthieno[3,2-c]pyrazol-5-yl)-N-[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;N-(5-Fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)pyridazin-3-amine;5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylazetidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;tert-Butyl3-(2-(2-((5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-5-methyl-4-oxo-4,5-dihydrothieno[2,3-d]pyridazin-7-yl)azetidine-1-carboxylate;2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-(3-fluorobicyclo[1.1.1]pentan-1-yl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one;5-(2-((5-(6-Ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-3-isopropyl-N,N,6-trimethyl-3H-thieno[2,3-d]imidazol-2-amine;N-(5-(2-Ethyl-2-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[6-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[5-(1-methylpyrrolidin-3-yl)oxypyridin-2-yl]pyrimidin-2-amine;5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(4-methylmorpholin-2-yl)pyridin-2-yl)pyrimidin-2-amine;N-[5-[1-(4-Ethylpiperazin-1-yl)ethyl]pyridin-2-yl]-5-fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;3-[6-[[5-Fluoro-4-(2-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl]amino]pyridin-3-yl]-1,4-dimethylpiperazin-2-one;((8aS)-6-(6-((5-Fluoro-4-(3-isopropyl-2,6-dimethyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-3(4H)-one;4-(2,6-Dimethyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)-N-[4-(4-ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoropyrimidin-2-amine;4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;N-[5-(4-Ethylpiperazin-1-yl)pyridin-2-yl]-5-fluoro-4-[7-propan-2-yl-3-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]pyrimidin-2-amine;2-(2-((5-(4-Ethylpiperazin-1-yl)pyridin-2-yl)amino)-5-fluoropyrimidin-4-yl)-7-isopropylthieno[3,2-b]pyridine-3-carbonitrile;5-Fluoro-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-4-(3-methyl-7-propan-2-ylthieno[3,2-c]pyridin-2-yl)pyrimidin-2-amine;N-[5-[(4-Ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine (isomer 1);5-Fluoro-N-[5-[-1-methylpiperidin-3-yl]pyridin-2-yl]-4-(6-methyl-3-propan-2-ylthieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine(isomer 2);4-(3-Isopropyl-2-methyl-3H-thieno[2,3-d]imidazol-5-yl)-5-methoxy-N-(5-(1-methylpiperidin-4-yl)pyridin-2-yl)pyrimidin-2-amine;N-(5-(1-Ethylpiperidin-4-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine; N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(3-isopropyl-3H-thieno[2,3-d]imidazol-5-yl)pyrimidin-2-amine;5-Chloro-4-(3-isopropyl-6-methyl-3H-thieno[2,3-d]imidazol-5-yl)-N-(5-(1-methylpiperidin-3-yl)pyridin-2-yl)pyrimidin-2-amine;2-(5-Fluoro-2-((5-(1-methylpiperidin-4-yl)pyridin-2-yl)amino)pyrimidin-4-yl)-7-isopropyl-3-methylthieno[3,2-c]pyridine 5-oxide; or a pharmaceutically acceptable salt thereof.
 42. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 43. A method of inhibiting CDK4 and CDK6comprising administering a compound according to claim 1, or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable composition thereof.
 44. A method for treating aCDK4-mediated and a CDK6-mediated disorder in a patient in need thereof,comprising administering to said patient a compound according to claim1, or a pharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable composition thereof.
 45. The method according to claim 44,wherein the CDK4-mediated and CDK6-mediated disorder is a cancer. 46.The method according to claim 45, wherein the cancer is breast cancer,malignant brain tumors, colon cancer, small-cell lung cancer,non-small-cell lung cancer, bladder cancer, ovarian cancer, prostatecancer, chronic lymphoid leukemia, lymphoma, myeloma, acute myeloidleukemia, secondary pancreatic cancer or secondary brain metastases. 47.The method according to claim 46, wherein the breast cancer is HR+/HER2−or HR+/HER2+ advanced or metastatic breast cancer; and the malignantbrain tumors are glioblastoma, astrocytoma, or pontine glioma.
 48. Themethod according to claim 44, wherein the patient is administered thepharmaceutically acceptable composition.
 49. The method according toclaim 44, wherein the administration is oral administration.
 50. Themethod according to claim 44, further comprising administering anadditional therapeutic agent to the patient.
 51. The method according toclaim 50, wherein the additional therapeutic agent is a PRMT5 inhibitor,a HER2 kinase inhibitor, an aromatase inhibitor, an estrogen receptorantagonist or an alkylating agent.
 52. The method according to claim 51,wherein the aromatase inhibitor is letrozole.
 53. The method accordingto claim 51 wherein estrogen receptor antagonist is fulvestrant.
 54. Themethod according to claim 51, wherein the alkylating agent istemozolomide.